Limitations of Use

JANUMET XR should not be used in patients with type 1 diabetes mellitus.
JANUMET XR 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 JANUMET XR. [See Warnings and Precautions (5.2).]

2.1 Recommended Dosing

• Take JANUMET XR orally once daily with a meal. Patients taking two JANUMET XR tablets should take the two tablets together once daily.
• Individualize the dosage of JANUMET XR on the basis of the patient’s current regimen, effectiveness, and tolerability.
• The maximum recommended daily dose is 100 mg of sitagliptin and 2000 mg of metformin hydrochloride (HCl) extended-release.
• The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1000 mg metformin HCl extended-release once daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin.
• The starting dose in patients already treated with metformin should provide 100 mg sitagliptin and the previously prescribed dose of metformin.
• For patients taking metformin HCl immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin and 1000 mg metformin HCl extended-release tablets taken together once daily.
• Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET (sitagliptin and metformin HCl immediate-release) and JANUMET XR.
• Do not split, crush or chew JANUMET XR tablets.

2.2 Recommendations for Use in Renal Impairment

• Assess renal function prior to initiation of JANUMET XR and periodically thereafter.
• JANUMET XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. Discontinue JANUMET XR if the patient's eGFR later falls below 30 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1)].
• Initiation of JANUMET XR in patients with an eGFR between 30 and 45 mL/min/1.73 m2 is not recommended.
• In patients taking JANUMET XR whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy and limit dose of the sitagliptin component to 50 mg once daily.

2.3 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue JANUMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart JANUMET XR if renal function is stable [see Warnings and Precautions (5.1)].

5.1 Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of JANUMET XR. In JANUMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis, and if these symptoms occur instruct them to discontinue JANUMET XR and report these symptoms to their health care provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

5.2 Pancreatitis

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin with or without metformin. After initiation of JANUMET XR, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUMET XR 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 JANUMET XR.

5.3 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 JANUMET XR 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 JANUMET XR.

5.4 Acute Renal Failure

There have been postmarketing reports of worsening renal function in patients taking sitagliptin with or without metformin, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy with JANUMET XR and at least annually thereafter, renal function should be assessed. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET XR discontinued if evidence of renal impairment is present. JANUMET XR is contraindicated in patients with severe renal impairment [see Contraindications (4) and Warnings and Precautions (5.1)].

5.5 Vitamin B12 Deficiency

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 measurements at 2- to 3-year intervals in patients on JANUMET XR and manage any abnormalities [see Adverse Reactions (6.1)].

5.6 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues

JANUMET XR may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue (e.g., sulfonylurea) [see Adverse Reactions (6)]. A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with JANUMET XR [see Drug Interactions (7)].

5.7 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET XR. 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 sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUMET XR, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See Adverse Reactions (6.2).]

Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUMET XR.

5.8 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.

5.9 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 JANUMET XR. If bullous pemphigoid is suspected, JANUMET XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

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.

6.2 Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of sitagliptin with metformin, sitagliptin, or metformin. 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; upper respiratory tract infection; 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; cholestatic, hepatocellular, and mixed hepatocellular liver injury; rhabdomyolysis.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

8.4 Pediatric Use

The safety and effectiveness of JANUMET XR 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 sitagliptin (N=95) was 0.06% compared to 0.23% in patients treated with placebo (N=95), a difference of -0.17% (95% CI: -0.62, 0.28). In studies 2 and 3, the mean baseline HbA1c was 8.0%, 15% of patients were on insulin and 72% were on metformin HCl doses of greater than 1,500 mg daily. At week 20, the change from baseline in HbA1c in patients treated with sitagliptin (N=107) was -0.23% compared to 0.09% in patients treated with placebo (N=113), a difference of -0.33% (95% CI: -0.70, 0.05).

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. JANUMET XR is not recommended in patients with hepatic impairment. [See Warnings and Precautions (5.1).]

Sitagliptin

Sitagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Sitagliptin phosphate monohydrate drug substance is used to manufacture JANUMET XR. 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-α]pyrazine phosphate (1:1) monohydrate with an empirical formula of C16H15F6N5O•H3PO4•H2O and a molecular weight of 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.

Metformin

Metformin HCl (N,N-dimethylimidodicarbonimidic diamide HCl) is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin HCl is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin HCl is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. The structural formula is as shown:

JANUMET XR

JANUMET XR is available as film-coated tablets containing:

• 64.25 mg sitagliptin monohydrate equivalent to 50 mg sitagliptin and 389.93 mg of metformin equivalent to 500 mg metformin HCl (JANUMET XR 50/500).
• 64.25 mg sitagliptin monohydrate equivalent to 50 mg sitagliptin and 779.86 mg of metformin equivalent to 1000 mg metformin HCl (JANUMET XR 50/1000).
• 128.5 mg sitagliptin monohydrate equivalent to 100 mg sitagliptin and 779.86 mg of metformin equivalent to 1000 mg metformin HCl (JANUMET XR 100/1000).

All doses of JANUMET XR contain the following inactive ingredients: povidone, hypromellose, colloidal silicon dioxide, sodium stearyl fumarate, propyl gallate, polyethylene glycol, and kaolin. The JANUMET XR 50 mg/500 mg tablet contains the additional inactive ingredient microcrystalline cellulose. In addition, the film coating for all doses contains the following inactive ingredients: hypromellose, hydroxypropyl cellulose, titanium dioxide, FD&C #2/Indigo Carmine Aluminum Lake and carnauba wax. The JANUMET XR 50 mg/1000 mg tablet film coating also contains the inactive ingredient yellow iron oxide.

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Metformin Extended-Release Compared to Metformin Immediate-Release in Patients with Type 2 Diabetes

In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group trial extended-release metformin HCl 1500 mg once daily, extended-release metformin HCl 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening), and extended-release metformin HCl 2000 mg once daily were compared to immediate-release metformin HCl 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening). This trial enrolled patients (n = 338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single anti-diabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglitinides), and patients (n = 368) receiving metformin HCl up to 1500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who were enrolled on monotherapy or combination antidiabetic therapy underwent a 6-week washout. Patients randomized to extended-release metformin HCl began titration from 1000 mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release metformin HCl initiated 500 mg twice daily for 1 week followed by 500 mg with breakfast and 1000 mg with dinner for the second week. The 3-week treatment period was followed by an additional 21-week period at the randomized dose. For HbA1c and fasting plasma glucose, each of the extended-release metformin regimens was at least as effective as immediate-release metformin. Additionally, once daily dosing of extended-release metformin was as effective as twice daily dosing of the immediate-release metformin formulation.

Sitagliptin and Metformin Immediate-Release Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise

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 and metformin immediate-release coadministration. Patients on an antihyperglycemic agent (N=541) 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 placebo, 100 mg of sitagliptin once daily, 500 mg or 1000 mg of metformin HCl immediate-release twice daily, or 50 mg of sitagliptin twice daily in combination with 500 mg or 1000 mg of metformin HCl immediate-release twice daily. Patients who failed to meet specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.

Sitagliptin and metformin immediate-release coadministration provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin immediate-release alone, and to sitagliptin alone (Table 9, Figure 1). For patients not on an antihyperglycemic agent at study entry, mean reductions from baseline in A1C were: sitagliptin 100 mg once daily, -1.1%; metformin HCl immediate-release 500 mg bid, -1.1%; metformin HCl immediate-release 1000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin HCl immediate-release 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin HCl immediate-release 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 immediate-release was similar to that in the groups given metformin alone or placebo.

* The Completers Population: least squares means adjusted for prior antihyperglycemic therapy and baseline value.

Figure 1: Mean Change from Baseline for A1C (%) over 24 Weeks with Sitagliptin and Metformin Immediate-Release, Alone and in Combination in Patients with Type 2 Diabetes Inadequately Controlled with Diet and Exercise*

Initial combination therapy or maintenance of combination therapy should be individualized and are left to the discretion of the health care provider.

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on the Combination of Metformin Immediate-Release 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 sitagliptin in combination with metformin immediate-release and rosiglitazone. Patients on dual therapy with metformin HCl immediate-release ≥1500 mg/day and rosiglitazone ≥4 mg/day or with metformin HCl immediate-release ≥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 HCl immediate-release ≥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 sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18.

In combination with metformin immediate-release and rosiglitazone, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin immediate-release and rosiglitazone (Table 12) at Week 18. At Week 54, mean reduction in A1C was -1.0% for patients treated with sitagliptin 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 sitagliptin 100 mg and 40% of patients treated with placebo. There was no significant difference between sitagliptin and placebo in body weight change.

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on the Combination of Metformin Immediate-Release and Insulin

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 sitagliptin as add-on to insulin therapy. Approximately 75% of patients were also taking metformin immediate-release. Patients entered a 2-week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin HCl immediate-release (≥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 sitagliptin (N=229) or placebo (N=233), 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.

Among patients also receiving metformin immediate-release, the median daily insulin (pre-mixed, intermediate or long acting) dose at baseline was 40 units in the sitagliptin-treated patients and 42 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. Patients receiving sitagliptin with metformin immediate-release and insulin had significant improvements in A1C, FPG and 2-hour PPG compared to patients receiving placebo with metformin immediate-release and insulin (Table 13). The adjusted mean change from baseline in body weight was -0.3 kg in patients receiving sitagliptin with metformin immediate-release and insulin and -0.2 kg in patients receiving placebo with metformin immediate-release and insulin. There was an increased rate of hypoglycemia in patients treated with sitagliptin. [See Warnings and Precautions (5.6); Adverse Reactions (6.1).]

Maintenance of Sitagliptin During Initiation and Titration of Insulin Glargine

A total of 746 patients with type 2 diabetes (mean baseline HbA1C 8.8%, disease duration 10.8 years) participated in a 30-week, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of continuing sitagliptin during the initiation and uptitration of insulin glargine. Patients who were on a stable dose of metformin HCl (≥1500 mg/day) in combination with a DPP-4 inhibitor and/or sulfonylurea but with inadequate glycemic control (A1C 7.5% to 11%) were enrolled in the study. Those on metformin and sitagliptin (100 mg/day) directly entered the double-blind treatment period; those on another DPP-4 inhibitor and/or on a sulfonylurea entered a 4-8 week run-in period in which they were maintained on metformin and switched to sitagliptin (100 mg); other DPP-4 inhibitors and sulfonylureas were discontinued. At randomization patients were randomized either to continue sitagliptin or to discontinue sitagliptin and switch to a matching placebo. On the day of randomization, insulin glargine was initiated at a dose of 10 units subcutaneously in the evening. Patients were instructed to uptitrate their insulin dose in the evening based on fasting blood glucose measurements to achieve a target of 72-100 mg/dL.

At 30 weeks, the mean reduction in A1C was greater in the sitagliptin group than in the placebo group (Table 14). At the end of the trial, 27.3% of patients in the sitagliptin group and 27.3% in the placebo group had a fasting plasma glucose (FPG) in the target range; there was no significant difference in insulin dose between arms.

Sitagliptin Add-on Therapy vs. Glipizide Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Immediate-Release

The efficacy of sitagliptin 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 HCl immediate-release monotherapy (dose of ≥1500 mg per day) which included washout of medications other than metformin immediate-release, 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 sitagliptin 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, sitagliptin and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 15). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of sitagliptin 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%).

* 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.

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

The incidence of hypoglycemia in the sitagliptin group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32.0%). Patients treated with sitagliptin 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).

Lactic Acidosis

Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue JANUMET XR immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about the importance of regular testing of renal function while receiving JANUMET XR. Instruct patients to inform their doctor that they are taking JANUMET XR prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions (5.1)].

Pancreatitis

Inform patients that acute pancreatitis has been reported during postmarketing use of JANUMET XR. Inform patients 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. Instruct patients to promptly discontinue JANUMET XR and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.2)].

Heart Failure

Inform patients of the signs and symptoms of heart failure. Before initiating JANUMET XR, ask patients about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their health care provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions (5.3)].

Vitamin B12 Deficiency

Inform patients about the importance of regular monitoring of hematological parameters while receiving JANUMET XR [see Warnings and Precautions (5.5)].

Hypoglycemia

Inform patients that the incidence of hypoglycemia is increased when sitagliptin with or without metformin is added to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy. Explain to patients receiving JANUMET XR in combination with these medications the risks of hypoglycemia, its symptoms and treatment and conditions that predispose to its development [see Warnings and Precautions (5.6)].

Hypersensitivity Reactions

Inform patients that allergic reactions have been reported during postmarketing use of sitagliptin, one of the components of JANUMET XR. 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 JANUMET XR and seek medical advice promptly.

Severe and Disabling Arthralgia

Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions (5.8)].

Bullous Pemphigoid

Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions (5.9)].

Administration Instructions

Inform patients that the tablets must be swallowed whole and never split, crushed or chewed.

Incompletely Dissolved Tablets in Feces

Inform patients that incompletely dissolved JANUMET XR tablets may be eliminated in the feces. Tell patients that, if they repeatedly see tablets in feces, they should report this finding to their health care provider. Assess adequacy of glycemic control if a patient reports repeatedly observing tablets in feces.

Females of Reproductive Age:

Inform females that treatment with JANUMET XR may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)].