1 INDICATIONS AND USAGE Sitagliptin tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use Sitagliptin tablets should not be used in patients with type 1 diabetes.

Sitagliptin tablets have 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 sitagliptin tablets [see Warnings and Precautions ( 5.1 )].

Sitagliptin 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 : Sitagliptin tablets should not be used in patients with type 1 diabetes ( 1 ) Sitagliptin tablets have not been studied in patients with a history of pancreatitis.

( 1 , 5.1 )

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 sitagliptin 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 sitagliptin compared to placebo.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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 sitagliptin were similar to placebo.

In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with sitagliptin 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 sitagliptin 100 mg daily, sitagliptin 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 sitagliptin 100 mg daily or placebo.

The adverse reactions, excluding hypoglycemia, reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin 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 Sitagliptin 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) Sitagliptin 100 mg Placebo N = 443 N = 363 Nasopharyngitis 23 (5.2) 12 (3.3) Combination with Pioglitazone (24 weeks) Sitagliptin 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) Sitagliptin 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) Sitagliptin 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) * Intent-to-treat population In the 24-week study of patients receiving sitagliptin 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 sitagliptin 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 sitagliptin 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 sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 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 sitagliptin was as follows: abdominal pain (sitagliptin 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 100 mg QD Metformin HCl 500 or 1,000 mg bid † Sitagliptin 50 mg bid + Metformin HCl 500 or 1,000 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) * Intent-to-treat population.

† Data pooled for the patients given the lower and higher doses of metformin.

In a 24-week study of initial therapy with sitagliptin 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 sitagliptin.

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=5,429) or corresponding (active or placebo) control (N=4,817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4,708 patient-years for sitagliptin and 4 patients with an event in 3,942 patient-years for control).

Hypoglycemia In the above studies (N=9), 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 sitagliptin 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 Sitagliptin 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) Sitagliptin 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) Sitagliptin 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) * Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population.

† Based on total number of events (i.e., a single patient may have had multiple events).

‡ Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure.

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 sitagliptin 100 mg and 0.9% in patients treated with placebo.

In the study of sitagliptin as add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on sitagliptin 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 sitagliptin and 1.0% in patients given add-on placebo.

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

In the study of sitagliptin as initial therapy with pioglitazone, one patient taking sitagliptin experienced a severe episode of hypoglycemia.

There were no severe hypoglycemia episodes reported in other studies except in the study involving coadministration with insulin.

In an additional, 30-week placebo-controlled, study of patients with type 2 diabetes inadequately controlled with metformin comparing the maintenance of sitagliptin 100 mg versus withdrawal of sitagliptin when initiating basal insulin therapy, the event rate and incidence of documented symptomatic hypoglycemia (blood glucose measurement ≤70 mg/dL) did not differ between the sitagliptin and placebo groups.

Laboratory Tests Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with sitagliptin 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 6,600 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 sitagliptin 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 sitagliptin [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 sitagliptin 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; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage ( 1 )] ; worsening renal function, including acute renal failure (sometimes requiring dialysis), and tubulointerstitial nephritis; severe and disabling arthralgia; bullous pemphigoid; constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus; mouth ulceration; stomatitis; rhabdomyolysis.