JANUVIA

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. Co-administration 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 T_max) 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 μM•hr, C_max was 950 nM, and apparent terminal half-life (t_1/2) 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 t_1/2 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 C_max 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 C_max by 18%.

Metformin: Co-administration 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: Co-administration 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 co-administered medications.

Metformin: Co-administration 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. Co-administration of a single 100 mg oral dose of JANUVIA and a single 600 mg oral dose of cyclosporine increased the AUC and C_max 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 DiabetesIntent-to-treat population using last observation on study prior to metformin rescue therapy.

	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 meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-0.5	0.1	-0.6	0.2
Difference from placebo (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)   (95% CI)	-0.6p<0.001 compared to placebo. (-0.8, -0.4)		-0.8p<0.001 compared to placebo. (-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 meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-13	7	-12	5
Difference from placebo (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)   (95% CI)	-20p<0.001 compared to placebo. (‑31, -9)		-17p<0.001 compared to placebo. (‑24, -10)
2-hour PPG (mg/dL)	Data not available.	Data not available.	N = 201	N = 204
Baseline (mean)			257	271
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)			-49	-2
Difference from placebo (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)   (95% CI)			-47p<0.001 compared to placebo. (-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 MetforminIntent-to-treat population using last observation on study prior to pioglitazone rescue therapy.

	JANUVIA 100 mg + Metformin	Placebo + Metformin
A1C (%)	N = 453	N = 224
Baseline (mean)	8.0	8.0
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy and baseline value.)	-0.7	-0.0
Difference from placebo + metformin (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy and baseline value.)   (95% CI)	-0.7p<0.001 compared to placebo + metformin. (-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 meanLeast squares means adjusted for prior antihyperglycemic therapy and baseline value.)	-17	9
Difference from placebo + metformin (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy and baseline value.)   (95% CI)	-25p<0.001 compared to placebo + metformin. (-31, -20)
2-hour PPG (mg/dL)	N = 387	N = 182
Baseline (mean)	275	272
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy and baseline value.)	-62	-11
Difference from placebo + metformin (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy and baseline value.)   (95% CI)	-51p<0.001 compared to placebo + metformin. (-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 TherapyIntent-to-treat population using last observation on study prior to glyburide (glibenclamide) rescue 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 meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	0.2	-0.7	-0.8	-1.1	-1.4	-1.9
Difference from placebo (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.) (95% CI)		-0.8p<0.001 compared to placebo. (-1.1, -0.6)	-1.0p<0.001 compared to placebo. (-1.2, -0.8)	-1.3p<0.001 compared to placebo. (-1.5, -1.1)	-1.6p<0.001 compared to placebo. (-1.8, -1.3)	-2.1p<0.001 compared to placebo. (-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 meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	6	-17	-27	-29	-47	-64
Difference from placebo (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.) (95% CI)		-23p<0.001 compared to placebo. (-33, -14)	-33p<0.001 compared to placebo. (-43, -24)	-35p<0.001 compared to placebo. (-45, -26)	-53p<0.001 compared to placebo. (-62, -43)	-70p<0.001 compared to placebo. (-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 meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	0	-52	-53	-78	-93	-117
Difference from placebo (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.) (95% CI)		-52p<0.001 compared to placebo. (-67, -37)	-54p<0.001 compared to placebo. (-69, -39)	-78p<0.001 compared to placebo. (-93, -63)	-93p<0.001 compared to placebo. (-107, -78)	-117p<0.001 compared to placebo. (-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 DiabetesAll Patients Treated Population: least squares means adjusted for prior antihyperglycemic therapy and baseline value.

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)The intent-to-treat analysis used the patients' last observation in the study prior to discontinuation.

	JANUVIA 100 mg	Glipizide
A1C (%)	N = 576	N = 559
Baseline (mean)	7.7	7.6
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline A1C value.)	-0.5	-0.6
FPG (mg/dL)	N = 583	N = 568
Baseline (mean)	166	164
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline A1C value.)	-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)The per protocol population (mean baseline A1C of 7.5%) included patients without major protocol violations who had observations at baseline and at Week 52.

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 PPARγ 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 PioglitazoneIntent-to-treat population using last observation on study prior to metformin rescue therapy.

	JANUVIA 100 mg + Pioglitazone	Placebo + Pioglitazone
A1C (%)	N = 163	N = 174
Baseline (mean)	8.1	8.0
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-0.9	-0.2
Difference from placebo + pioglitazone (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)   (95% CI)	-0.7p<0.001 compared to placebo + pioglitazone. (-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 meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-17	1
Difference from placebo + pioglitazone (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)   (95% CI)	-18p<0.001 compared to placebo + pioglitazone. (-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 Intent-to-treat population using last observation on study.

	JANUVIA 100 mg + Pioglitazone	Pioglitazone
A1C (%)	N = 251	N = 246
Baseline (mean)	9.5	9.4
Change from baseline (adjusted meanLeast squares means adjusted for baseline value.)	-2.4	-1.5
Difference from pioglitazone (adjusted meanLeast squares means adjusted for baseline value.) (95% CI)	-0.9 p<0.001 compared to placebo + pioglitazone. (-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 meanLeast squares means adjusted for baseline value.)	-63	-40
Difference from pioglitazone (adjusted meanLeast squares means adjusted for baseline value.) (95% CI)	-23 p<0.001 compared to placebo + pioglitazone. (-30, -15)
2-hour PPG (mg/dL)	N = 216	N = 211
Baseline (mean)	283	284
Change from baseline (adjusted meanLeast squares means adjusted for baseline value.)	-114	-69
Difference from pioglitazone (adjusted meanLeast squares means adjusted for baseline value.) (95% CI)	-45 p<0.001 compared to placebo + pioglitazone. (-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 RosiglitazoneIntent-to-treat population using last observation on study prior to glipizide (or other sulfonylurea) rescue therapy.

	JANUVIA 100 mg + Metformin + Rosiglitazone	Placebo + Metformin + Rosiglitazone
A1C (%)	N = 176	N = 93
Baseline (mean)	8.8	8.7
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-1.0	-0.4
Difference from placebo + rosiglitazone + metformin (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.) (95% CI)	-0.7 p<0.001 compared to placebo + metformin + rosiglitazone. (-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 meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-30	-11
Difference from placebo + rosiglitazone + metformin (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.) (95% CI)	-18 p<0.001 compared to placebo + metformin + rosiglitazone. (-26, -10)
2-hour PPG (mg/dL)	N = 152	N = 80
Baseline (mean)	256	248
Change from baseline (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-59	-21
Difference from placebo + rosiglitazone + metformin (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.) (95% CI)	-39 p<0.001 compared to placebo + metformin + rosiglitazone. (-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 (5.3); 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 MetforminIntent-to-treat population using last observation on study prior to pioglitazone rescue therapy.

	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 meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-0.3	0.3	-0.6	0.3
Difference from placebo (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)   (95% CI)	-0.6p<0.001 compared to placebo. (-0.8, -0.3)		-0.9p<0.001 compared to placebo. (-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 meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)	-1	18	-8	13
Difference from placebo (adjusted meanLeast squares means adjusted for prior antihyperglycemic therapy status and baseline value.)   (95% CI)	-19p<0.01 compared to placebo. (-32, -7)		-21p<0.001 compared to placebo. (-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 (5.3); Adverse Reactions (6.1).]

Table 12: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA as Add-on Combination Therapy with InsulinIntent-to-treat population using last observation on study prior to rescue therapy.

	JANUVIA 100 mg + Insulin (+/- Metformin)	Placebo + Insulin (+/- Metformin)
A1C (%)	N = 305	N = 312
Baseline (mean)	8.7	8.6
Change from baseline (adjusted mean Least squares means adjusted for metformin use at the screening visit (yes/no), type of insulin used at the screening visit (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value. )	-0.6	-0.1
Difference from placebo (adjusted mean Least squares means adjusted for metformin use at the screening visit (yes/no), type of insulin used at the screening visit (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value. , Treatment by stratum interaction was not significant (p>0.10) for metformin stratum and for insulin stratum.) (95% CI)	-0.6p<0.001 compared to placebo. (-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 Least squares means adjusted for metformin use at the screening visit (yes/no), type of insulin used at the screening visit (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value. )	-18	-4
Difference from placebo (adjusted mean Least squares means adjusted for metformin use at the screening visit (yes/no), type of insulin used at the screening visit (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value. ) (95% CI)	-15p<0.001 compared to placebo. (-23, -7)
2-hour PPG (mg/dL)	N = 240	N = 257
Baseline (mean)	291	292
Change from baseline (adjusted mean Least squares means adjusted for metformin use at the screening visit (yes/no), type of insulin used at the screening visit (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value. )	-31	5
Difference from placebo (adjusted mean Least squares means adjusted for metformin use at the screening visit (yes/no), type of insulin used at the screening visit (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value. ) (95% CI)	-36p<0.001 compared to placebo. (-47, -25)

16 HOW SUPPLIED/STORAGE AND HANDLING

No. 6737 — Tablets JANUVIA, 25 mg, are pink, round, film-coated tablets with "221" on one side. They are supplied as follows:

NDC 0006-0221-31 unit-of-use bottles of 30

NDC 0006-0221-54 unit-of-use bottles of 90

NDC 0006-0221-28 unit dose blister packages of 100.

No. 6738 — Tablets JANUVIA, 50 mg, are light beige, round, film-coated tablets with "112" on one side. They are supplied as follows:

NDC 0006-0112-31 unit-of-use bottles of 30

NDC 0006-0112-54 unit-of-use bottles of 90

NDC 0006-0112-28 unit dose blister packages of 100.

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

NDC 0006-0277-31 unit-of-use bottles of 30

NDC 0006-0277-54 unit-of-use bottles of 90

NDC 0006-0277-33 unit-of-use blister calendar package of 30

NDC 0006-0277-28 unit dose blister packages of 100

NDC 0006-0277-82 bottles of 1000.

Storage

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

17 PATIENT COUNSELING INFORMATION

See 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 seek medical advice promptly.

Patients should be informed that acute pancreatitis has been reported during postmarketing use of JANUVIA. Patients should be informed that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue JANUVIA and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.1)].

Patients should be informed that the incidence of hypoglycemia is increased when JANUVIA is added to a sulfonylurea or insulin and that a lower dose of the sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Patients should be informed that allergic reactions have been reported during postmarketing use of JANUVIA. If symptoms of allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking JANUVIA and seek medical advice promptly.

Physicians should instruct their patients to read the Medication Guide before starting JANUVIA therapy and to reread each time the prescription is renewed. Patients should be instructed to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.

17.2 Laboratory Tests

Patients should be informed that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C levels, with a goal of decreasing these levels towards the normal range. A1C is especially useful for evaluating long-term glycemic control. Patients should be informed of the potential need to adjust dose based on changes in renal function tests over time.

Distributed by: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

US Patent Nos.: 6,699,871 and 7,326,708

Copyright © 2006, 2007, 2009, 2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.

uspi-mk0431-t-1308r012

Medication Guide

JANUVIA^® (jah-NEW-vee-ah)
(sitagliptin)
Tablets

Read this Medication Guide carefully before you start taking JANUVIA and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about JANUVIA, ask your doctor or pharmacist.

What is the most important information I should know about JANUVIA?

Serious side effects can happen in people taking JANUVIA, including 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
• •stones in your gallbladder (gallstones)
• •a history of alcoholism
• •high blood triglyceride levels
• •kidney problems

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.

What is JANUVIA?

• •JANUVIA is a prescription medicine used along with diet and exercise to lower blood sugar in adults with type 2 diabetes.
• •JANUVIA is not for people with type 1 diabetes.
• •JANUVIA is not for people with diabetic ketoacidosis (increased ketones in your blood or urine).
• •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.
• •It is not known if JANUVIA is safe and effective when used in children under 18 years of age.

Who should not take JANUVIA?

Do not take JANUVIA if:

• •you are allergic to any of the ingredients in JANUVIA. See the end of this Medication Guide for a complete list of ingredients in JANUVIA.
  
  Symptoms of a serious allergic reaction to JANUVIA may include:
  • •rash
  • •raised red patches on your skin (hives)
  • •swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing

What should I tell my doctor before taking 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 non-prescription 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 see how well your kidneys are working. Your doctor may change your dose of JANUVIA based on the results of your blood tests.
• • Your doctor may tell you to take JANUVIA along with other diabetes medicines. Low blood sugar can happen more often when JANUVIA is taken with certain other diabetes medicines. See "What are the possible side effects of JANUVIA?".
• • If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of JANUVIA at the same time.
• • If you take too much JANUVIA, call your doctor or local Poison Control Center right away.
• • When your body is under some types of stress, such as fever, trauma (such as a car accident), infection or surgery, the amount of diabetes medicine that you need may change. Tell your doctor right away if you have any of these conditions and follow your doctor's instructions.
• • Check your blood sugar as your doctor tells you to.
• • Stay on your prescribed diet and exercise program while taking JANUVIA.
• • Talk to your doctor about how to prevent, recognize and manage low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and problems you have because of your diabetes.
• •Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C.

What are the possible side effects of JANUVIA?

Serious side effects have happened in people taking JANUVIA.

• •See "What is the most important information I should know about JANUVIA?".
  
  
• • Low blood sugar (hypoglycemia). If you take JANUVIA with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you use JANUVIA. Signs and symptoms of low blood sugar may include:

The most common side effects of JANUVIA include:

• •upper respiratory infection
• •stuffy or runny nose and sore throat
• •headache

JANUVIA may have other side effects, including:

• •stomach upset and diarrhea
• •swelling of the hands or legs, when JANUVIA is used with rosiglitazone (Avandia^®). Rosiglitazone is another type of diabetes medicine.

These are not all the possible side effects of JANUVIA. For more information, ask your doctor or pharmacist.

Tell your doctor if you have any side effect that bothers you, is unusual or does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store 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.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

US Patent Nos.: 6,699,871 and 7,326,708

The trademarks depicted herein are owned by their respective companies.

Copyright © 2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.

Revised: 08/2013

usmg-mk0431-t-1308r012

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