Sitagliptin and Metformin Hydrochloride

WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions ( 5.1 )]. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration ( 2.2 ), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)]. If metformin-associated lactic acidosis is suspected, immediately discontinue sitagliptin and metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions ( 5.1 )]. WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning. Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL. ( 5.1 ) Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the Full Prescribing Information. (5.1 ) If lactic acidosis is suspected, discontinue sitagliptin and metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Lactic Acidosis: See Boxed warning. ( 5.1 ) Pancreatitis: There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue sitagliptin and metformin hydrochloride tablets. ( 5.2 ) Heart Failure: Has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of sitagliptin and metformin hydrochloride tablets in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. ( 5.3 ) Acute Renal Failure: Has been reported postmarketing, sometimes requiring dialysis. Before initiating sitagliptin and metformin hydrochloride tablets and at least annually thereafter, assess renal function. ( 5.4 ) Vitamin B 12 Deficiency : Metformin may lower vitamin B 12 levels. Measure hematologic parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. ( 5.5 ) Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues: Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. A lower dose of insulin or insulin secretagogue may be required. ( 5.6 ) Hypersensitivity Reactions: There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Promptly stop sitagliptin and metformin hydrochloride tablets, assess for other potential causes, institute appropriate monitoring and treatment. ( 5.7 ) Severe and Disabling Arthralgia: Has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.8 ) Bullous Pemphigoid: There have been postmarketing reports requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue sitagliptin and metformin hydrochloride tablets. ( 5.9 ) 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 sitagliptin and metformin hydrochloride tablets. In sitagliptin and metformin hydrochloride-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl 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 sitagliptin and metformin hydrochloride tablets 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: Renal Impairment The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )]: Before initiating sitagliptin and metformin hydrochloride tablets, obtain an estimated glomerular filtration rate (eGFR). Sitagliptin and metformin hydrochloride tablets are contraindicated in patients with an eGFR below 30 mL/min/1.73 m 2 [see Contraindications ( 4 )]. Sitagliptin and metformin hydrochloride tablets are not recommended in patients with an eGFR between 30 and less than 45 mL/min/1.73 m 2 because these patients require a lower dosage of sitagliptin than what is available in the fixed combination sitagliptin and metformin hydrochloride tablets product. Obtain an eGFR at least annually in all patients taking sitagliptin and metformin hydrochloride tablets. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. Drug Interactions The concomitant use of sitagliptin and metformin hydrochloride tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions ( 7 )]. Therefore, consider more frequent monitoring of patients. Age 65 or Greater The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations ( 8.5 )]. Radiological Studies with Contrast Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop sitagliptin and metformin hydrochloride tablets 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 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart sitagliptin and metformin hydrochloride tablets if renal function is stable. Surgery and Other Procedures Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Sitagliptin and metformin hydrochloride tablets should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue sitagliptin and metformin hydrochloride tablets. Excessive Alcohol Intake Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving sitagliptin and metformin hydrochloride tablets. Hepatic Impairment Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of sitagliptin and metformin hydrochloride tablets in patients with clinical or laboratory evidence of hepatic disease. 5.2 Pancreatitis There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin and metformin hydrochloride tablets. After initiation of sitagliptin and metformin hydrochloride tablets, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, sitagliptin and metformin hydrochloride tablets 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 sitagliptin and metformin hydrochloride tablets. 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 sitagliptin and metformin hydrochloride tablets 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 sitagliptin and metformin hydrochloride tablets. 5.4 Acute Renal Failure There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy with sitagliptin and metformin hydrochloride tablets 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 sitagliptin and metformin hydrochloride tablets discontinued if evidence of renal impairment is present. Sitagliptin and metformin hydrochloride tablets are contraindicated in patients with severe renal impairment [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . 5.5 Vitamin B 12 Deficiency In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 measurements at 2- to 3-year intervals in patients on sitagliptin and metformin tablets and manage any abnormalities [see Adverse Reactions ( 6.1 )]. 5.6 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Sitagliptin and metformin hydrochloride tablets 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 sitagliptin and metformin hydrochloride tablets [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 sitagliptin and metformin hydrochloride tablets. 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 sitagliptin and metformin hydrochloride tablets, assess for other potential causes for the event, and institute alternative treatment for diabetes [see Adverse Reactions( 6.2 )]. Angioedema has also been reported with other DPP-4 inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with sitagliptin and metformin hydrochloride. 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 sitagliptin and metformin hydrochloride tablets. If bullous pemphigoid is suspected, sitagliptin and metformin hydrochloride tablets should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: Lactic Acidosis [see Warnings and Precautions ( 5.1 )] Pancreatitis [see Warnings and Precautions ( 5.2 )] Heart Failure [see Warnings and Precautions ( 5.3 )] Acute Renal Failure [see Warnings and Precautions ( 5.4 )] Vitamin B 12 Deficiency [see Warnings and Precautions ( 5.5 )] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions ( 5.6 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] Severe and Disabling Arthralgia [see Warnings and Precautions ( 5.8 )] Bullous Pemphigoid [see Warnings and Precautions ( 5.9 )] The most common adverse reactions reported in ≥5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 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. Sitagliptin and Metformin Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise Table 1 summarizes the most common (≥5% of patients) adverse reactions reported (regardless of investigator assessment of causality) in a 24-week placebo-controlled factorial study in which sitagliptin and metformin were coadministered to patients with type 2 diabetes inadequately controlled on diet and exercise. Table 1: Sitagliptin and Metformin Coadministered to Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo) * Number of Patients (%) Placebo Sitagliptin 100 mg once daily Metformin HCl 500 mg/ Metformin HCl 1,000 mg twice daily † Sitagliptin 50 mg twice daily + Metformin HCl 500 mg/ Metformin HCl 1,000 mg twice daily † N = 176 N = 179 N = 364 † N = 372 † * Intent-to-treat population. † Data pooled for the patients given the lower and higher doses of metformin. Diarrhea 7 (4.0) 5 (2.8) 28 (7.7) 28 (7.5) Upper Respiratory Tract 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) Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin regimen, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo. Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin, 1.9%; placebo and metformin, 2.5%). Gastrointestinal Adverse Reactions The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin were similar to those reported for patients treated with metformin alone. See Table 2. Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of Causality) Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin Number of Patients (%) Study of Sitagliptin and Metformin in Patients Inadequately Controlled on Diet and Exercise Study of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Alone Placebo Sitagliptin 100 mg once daily Metformin HCl 500 mg/ Metformin HCl 1,000 mg twice daily * Sitagliptin 50 mg twice daily + Metformin HCl 500 mg/ Metformin HCl 1,000 mg twice daily * Placebo and Metformin HCl ≥1,500 mg daily Sitagliptin 100 mg once daily and Metformin HCl ≥1,500 mg daily N = 176 N = 179 N = 364 N = 372 N = 237 N = 464 * Data pooled for the patients given the lower and higher doses of metformin. † Abdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy. Diarrhea 7 (4.0) 5 (2.8) 28 (7.7) 28 (7.5) 6 (2.5) 11 (2.4) Nausea 2 (1.1) 2 (1.1) 20 (5.5) 18 (4.8) 2 (0.8) 6 (1.3) Vomiting 1 (0.6) 0 (0.0) 2 (0.5) 8 (2.2) 2 (0.8) 5 (1.1) Abdominal Pain † 4 (2.3) 6 (3.4) 14 (3.8) 11 (3.0) 9 (3.8) 10 (2.2) Sitagliptin in Combination with Metformin and Glimepiride In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and glimepiride (sitagliptin, N=116; placebo, N=113), 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: hypoglycemia (Table 3) and headache (6.9%, 2.7%). Sitagliptin in Combination with Metformin and Rosiglitazone In a placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse reactions reported regardless of investigator assessment of causality through Week 18 in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). 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%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%). Sitagliptin in Combination with Metformin and Insulin In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3). Hypoglycemia In the above studies (N=5), adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When the combination of sitagliptin and metformin was coadministered with a sulfonylurea or with insulin, the percentage of patients reporting at least one adverse reaction of hypoglycemia was higher than that observed with placebo and metformin coadministered with a sulfonylurea or with insulin (Table 3). Table 3: Incidence and Rate of Hypoglycemia * (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Clinical Studies of Sitagliptin in Combination with Metformin Coadministered with Glimepiride or Insulin * 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. Add-On to Glimepiride + Metformin (24 weeks) Sitagliptin 100 mg + Metformin + Glimepiride Placebo + Metformin + Glimepiride N = 116 N = 113 Overall (%) 19 (16.4) 1 (0.9) Rate (episodes/patient-year) † 0.82 0.02 Severe (%) ‡ 0 (0.0) 0 (0.0) Add-On to Insulin + Metformin (24 weeks) Sitagliptin 100 mg + Metformin + Insulin Placebo + Metformin + Insulin N = 229 N = 233 Overall (%) 35 (15.3) 19 (8.2) Rate (episodes/patient-year) † 0.98 0.61 Severe (%) ‡ 1 (0.4) 1 (0.4) The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes inadequately controlled on diet and exercise 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 patients with type 2 diabetes inadequately controlled on metformin alone, the overall incidence of adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin and 2.1% in patients given add-on placebo. In the study of sitagliptin and add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on sitagliptin and 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% in patients given add-on placebo. 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. Vital Signs and Electrocardiograms With the combination of sitagliptin and metformin, no clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed. Pancreatitis 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). Sitagliptin The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis. Metformin The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. Laboratory Tests Sitagliptin The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin (7.6%) compared to patients treated with placebo and metformin (8.7%). In most but not all studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs placebo; mean baseline WBC approximately 6,600 cells/microL) was observed due to a small increase in neutrophils. This change in laboratory parameters is not considered to be clinically relevant. Metformin In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. 6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of sitagliptin and metformin hydrochloride, 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.

<table frame="box" rules="all" width="70%"><caption>Table 1: Sitagliptin and Metformin Coadministered to Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in &#x2265;5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo) <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-1">*</linkHtml></caption><thead><tr><th align="left" valign="top"/><th align="center" colspan="4" valign="top">Number of Patients (%)</th></tr><tr><th align="center" valign="middle"/><th align="center" valign="middle">Placebo</th><th align="center" valign="middle">Sitagliptin 100 mg once daily</th><th align="center" valign="middle">Metformin HCl 500 mg/ Metformin HCl 1,000 mg twice daily <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-2">&#x2020;</linkHtml></th><th align="center" valign="middle">Sitagliptin 50 mg twice daily + Metformin HCl 500 mg/ Metformin HCl 1,000 mg twice daily <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-2">&#x2020;</linkHtml></th></tr><tr><th align="left" valign="top"/><th align="center" valign="top">N = 176</th><th align="center" valign="top">N = 179</th><th align="center" valign="top">N = 364 <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-2">&#x2020;</linkHtml></th><th align="center" valign="top">N = 372 <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-2">&#x2020;</linkHtml></th></tr></thead><tfoot><tr><td align="left" colspan="5"><linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-reference-1">*</linkHtml>Intent-to-treat population. <paragraph/><linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-reference-2">&#x2020;</linkHtml>Data pooled for the patients given the lower and higher doses of metformin. </td></tr></tfoot><tbody><tr><td align="left" valign="top">Diarrhea</td><td align="center" valign="top">7 (4.0)</td><td align="center" valign="top">5 (2.8)</td><td align="center" valign="top">28 (7.7)</td><td align="center" valign="top">28 (7.5)</td></tr><tr><td align="left" valign="top">Upper Respiratory Tract Infection</td><td align="center" valign="top">9 (5.1)</td><td align="center" valign="top">8 (4.5)</td><td align="center" valign="top">19 (5.2)</td><td align="center" valign="top">23 (6.2)</td></tr><tr><td align="left" valign="top">Headache</td><td align="center" valign="top">5 (2.8)</td><td align="center" valign="top">2 (1.1)</td><td align="center" valign="top">14 (3.8)</td><td align="center" valign="top">22 (5.9)</td></tr></tbody></table>

<table frame="box" rules="all" width="80%"><caption>Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of Causality) Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin</caption><thead><tr><th align="left" valign="top"/><th align="center" colspan="6" valign="top">Number of Patients (%)</th></tr><tr><th align="left" valign="top"/><th align="center" colspan="4" valign="middle">Study of Sitagliptin and Metformin in Patients Inadequately Controlled on Diet and Exercise</th><th align="center" colspan="2" valign="top">Study of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Alone</th></tr><tr><th align="left" valign="top"/><th align="center" valign="middle">Placebo</th><th align="center" valign="middle">Sitagliptin 100 mg once daily</th><th align="center" valign="middle">Metformin HCl 500 mg/ Metformin HCl 1,000 mg twice daily <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-3">*</linkHtml></th><th align="center" valign="middle">Sitagliptin 50 mg twice daily + Metformin HCl 500 mg/ Metformin HCl 1,000 mg twice daily <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-3">*</linkHtml></th><th align="center" valign="top">Placebo and Metformin HCl &#x2265;1,500 mg daily</th><th align="center" valign="top">Sitagliptin 100 mg once daily and Metformin HCl &#x2265;1,500 mg daily</th></tr><tr><th align="left" valign="top"/><th align="center" valign="top">N = 176</th><th align="center" valign="top">N = 179</th><th align="center" valign="top">N = 364</th><th align="center" valign="top">N = 372</th><th align="center" valign="top">N = 237</th><th align="center" valign="top">N = 464</th></tr></thead><tfoot><tr><td align="left" colspan="7"><linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-reference-3">*</linkHtml>Data pooled for the patients given the lower and higher doses of metformin. <paragraph/><linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-reference-4">&#x2020;</linkHtml>Abdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy. </td></tr></tfoot><tbody><tr><td align="left" valign="top">Diarrhea</td><td align="center" valign="top">7 (4.0)</td><td align="center" valign="top">5 (2.8)</td><td align="center" valign="top">28 (7.7)</td><td align="center" valign="top">28 (7.5)</td><td align="center" valign="top">6 (2.5)</td><td align="center" valign="top">11 (2.4)</td></tr><tr><td align="left" valign="top">Nausea</td><td align="center" valign="top">2 (1.1)</td><td align="center" valign="top">2 (1.1)</td><td align="center" valign="top">20 (5.5)</td><td align="center" valign="top">18 (4.8)</td><td align="center" valign="top">2 (0.8)</td><td align="center" valign="top">6 (1.3)</td></tr><tr><td align="left" valign="top">Vomiting</td><td align="center" valign="top">1 (0.6)</td><td align="center" valign="top">0 (0.0)</td><td align="center" valign="top">2 (0.5)</td><td align="center" valign="top">8 (2.2)</td><td align="center" valign="top">2 (0.8)</td><td align="center" valign="top">5 (1.1)</td></tr><tr><td align="left" valign="top">Abdominal Pain <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-4">&#x2020;</linkHtml></td><td align="center" valign="top">4 (2.3)</td><td align="center" valign="top">6 (3.4)</td><td align="center" valign="top">14 (3.8)</td><td align="center" valign="top">11 (3.0)</td><td align="center" valign="top">9 (3.8)</td><td align="center" valign="top">10 (2.2)</td></tr></tbody></table>

<table border="0" frame="box" rules="all" width="60%"><caption>Table 3: Incidence and Rate of Hypoglycemia <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-5">*</linkHtml>(Regardless of Investigator Assessment of Causality) in Placebo-Controlled Clinical Studies of Sitagliptin in Combination with Metformin Coadministered with Glimepiride or Insulin </caption><tfoot><tr><td align="left" colspan="3"> <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-reference-5">*</linkHtml>Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required: Intent-to-treat population. <paragraph/><linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-reference-6">&#x2020;</linkHtml>Based on total number of events (i.e., a single patient may have had multiple events). <paragraph/><linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-reference-7">&#x2021;</linkHtml>Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure. </td></tr></tfoot><tbody><tr><td align="left" valign="top"><content styleCode="bold">Add-On to Glimepiride + Metformin</content>(24 weeks) </td><td align="center" valign="top"><content styleCode="bold">Sitagliptin 100 mg + Metformin + Glimepiride</content></td><td align="center" valign="top"><content styleCode="bold">Placebo + Metformin + Glimepiride</content></td></tr><tr><td align="left" valign="top"/><td align="center" valign="top">N = 116</td><td align="center" valign="top">N = 113</td></tr><tr><td align="left" valign="top">Overall (%)</td><td align="center" valign="top">19 (16.4)</td><td align="center" valign="top">1 (0.9)</td></tr><tr><td align="left" valign="top">Rate (episodes/patient-year) <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-6">&#x2020;</linkHtml></td><td align="center" valign="top">0.82</td><td align="center" valign="top">0.02</td></tr><tr><td align="left" valign="top">Severe (%) <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-7">&#x2021;</linkHtml></td><td align="center" valign="top">0 (0.0)</td><td align="center" valign="top">0 (0.0)</td></tr><tr><td align="left" valign="top"><content styleCode="bold">Add-On to Insulin + Metformin</content>(24 weeks) </td><td align="center" valign="top"><content styleCode="bold">Sitagliptin 100 mg + Metformin + Insulin</content></td><td align="center" valign="top"><content styleCode="bold">Placebo + Metformin + Insulin</content></td></tr><tr><td align="left" valign="top"/><td align="center" valign="top">N = 229</td><td align="center" valign="top">N = 233</td></tr><tr><td align="left" valign="top">Overall (%)</td><td align="center" valign="top">35 (15.3)</td><td align="center" valign="top">19 (8.2)</td></tr><tr><td align="left" valign="top">Rate (episodes/patient-year) <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-6">&#x2020;</linkHtml></td><td align="center" valign="top">0.98</td><td align="center" valign="top">0.61</td></tr><tr><td align="left" valign="top">Severe (%) <linkHtml href="http://torapps12.apotex.ca:8180/labelbridge-1.5/xslt?clear-stylesheet-cache=yes&amp;mode=&amp;style=styles/spl-revised.xsl&amp;print_preview=yes&amp;versionId=806&amp;xopus_mode=&amp;lb_id=1#footnote-7">&#x2021;</linkHtml></td><td align="center" valign="top">1 (0.4)</td><td align="center" valign="top">1 (0.4)</td></tr></tbody></table>