Metformin hydrochloride

1 INDICATIONS AND USAGE ZITUVIMET is a combination of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: ZITUVIMET is not recommended in patients with type 1 diabetes mellitus. ( 1 ) ZITUVIMET has not been studied in patients with a history of pancreatitis. ( 1 ) ZITUVIMET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use ZITUVIMET is not recommended in patients with type 1 diabetes mellitus. ZITUVIMET 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 ZITUVIMET. [see Warnings and Precautions ( 5.2 )].

2 DOSAGE AND ADMINISTRATION Take ZITUVIMET orally twice daily with meals. ( 2.1 ) Individualize the dosage of ZITUVIMET on the basis of the patient's current regimen, effectiveness, and tolerability. ( 2.1 ) The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin HCl. ( 2.1 ) The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin and 500 mg metformin HCl twice daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin. ( 2.1 ) The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin HCl 850 mg twice daily, the recommended starting dose of ZITUVIMET is 50 mg sitagliptin and 1,000 mg metformin HCl twice daily. ( 2.1 ) Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) ( 2.2 ) ○ Do not use in patients with eGFR below 30 mL/min/1.73 m 2 ○ ZITUVIMET is not recommended in patients with eGFR between 30 and less than 45 mL/min/1.73 m 2 . ZITUVIMET may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.3 ) 2.1 Recommended Dosage Take ZITUVIMET orally twice daily with meals. Individualize the dosage of ZITUVIMET on the basis of the patient's current regimen, effectiveness, and tolerability. The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin hydrochloride (HCl). Do not split or divide ZITUVIMET tablets. The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin and 500 mg metformin HCl twice 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 sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin HCl 850 mg twice daily, the recommended starting dose of ZITUVIMET is 50 mg sitagliptin and 1,000 mg metformin HCl twice daily. 2.2 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of ZITUVIMET and periodically thereafter. ZITUVIMET is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. ZITUVIMET is 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 ZITUVIMET product. 2.3 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue ZITUVIMET 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 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 ZITUVIMET if renal function is stable [see Warnings and Precautions ( 5.1 )].

3 DOSAGE FORMS AND STRENGTHS ZITUVIMET Tablets: • sitagliptin 50 mg and metformin HCl 500 mg tablets • sitagliptin 50 mg and metformin HCl 1,000 mg tablets ( 3 ) Tablets: sitagliptin 50 mg and metformin HCl 500 mg tablets are white to off-white, oval shaped, biconvex, film coated tablets debossed with "1786" on one side and plain on the other side. sitagliptin 50 mg and metformin HCl 1,000 mg tablets are reddish brown, oval shaped, biconvex, film coated tablets debossed with "1787" on one side and plain on the other side.

4 CONTRAINDICATIONS Severe renal impairment: (eGFR below 30 mL/min/1.73 m 2 ) ( 4) Metabolic acidosis, including diabetic ketoacidosis. ( 4 ) History of a serious hypersensitivity reaction to ZITUVIMET, sitagliptin, or metformin, such as anaphylaxis or angioedema. (4) ZITUVIMET is contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [see Warnings and Precautions ( 5.1 )]. Acute or chronic metabolic acidosis, including diabetic ketoacidosis. History of a serious hypersensitivity reaction to sitagliptin, metformin, or any of the excipients in ZITUVIMET. Serious hypersensitivity reactions including anaphylaxis or angioedema have been reported. [see Warnings and Precautions ( 5.7 ) and Adverse Reactions ( 6.2 )].

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 ZITUVIMET. ( 5.2 ) Heart Failure : Has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of ZITUVIMET 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 ZITUVIMET 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 ZITUVIMET, 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 ZITUVIMET. ( 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 ZITUVIMET. In ZITUVIMET 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 ZITUVIMET 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 ) and Clinical Pharmacology ( 12.3 )]: Before initiating ZITUVIMET, obtain an estimated glomerular filtration rate (eGFR). ZITUVIMET is contraindicated in patients with an eGFR below 30 mL/min/1.73 m 2 [see Contraindications ( 4 )]. ZITUVIMET is 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 ZITUVIMET product. Obtain an eGFR at least annually in all patients taking ZITUVIMET. 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 ZITUVIMET 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 ZITUVIMET 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 ZITUVIMET 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. ZITUVIMET 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 ZITUVIMET. 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 ZITUVIMET. 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 ZITUVIMET in patients with clinical or laboratory evidence of hepatic disease. Mitochondrial Diseases: Metformin may increase the risk of lactic acidosis in patients with mitochondrial diseases such as mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) syndrome and maternally inherited diabetes and deafness (MIDD). ZITUVIMET is not recommended in patients with mitochondrial diseases such as MELAS syndrome and MIDD. . If a patient taking ZITUVIMET develops elevated lactic acid levels (with or without accompanying neurologic signs and symptoms), discontinue ZITUVIMET. Depending on the clinical context, consider evaluating the patient for MELAS, MIDD, or other mitochondrial disease. 5.2 Pancreatitis There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking ZITUVIMET. After initiation of ZITUVIMET, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, sitagliptin 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 ZITUVIMET. 5.3 Heart Failure An association between 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 ZITUVIMET 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 ZITUVIMET. 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 ZITUVIMET 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 ZITUVIMET discontinued if evidence of renal impairment is present. ZITUVIMET 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 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 ZITUVIMET and manage any abnormalities [see Adverse Reactions ( 6.1 )]. 5.6 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues ZITUVIMET 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 ZITUVIMET [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 ZITUVIMET. 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 ZITUVIMET, 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 ZITUVIMET. 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 ZITUVIMET. If bullous pemphigoid is suspected, ZITUVIMET 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 prescribing information: 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 B12 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 )] Most common adverse reactions (incidence ≥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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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. Common Adverse Reactions Sitagliptin and Metformin Coadministration in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise Table 1 summarizes the most common (≥5% of patients) adverse reactions reported in a 24-week placebo-controlled factorial trial in which sitagliptin and metformin were coadministered to patients with type 2 diabetes mellitus inadequately controlled on diet and exercise. Table 1: Sitagliptin and Metformin Coadministered to Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise: Adverse Reactions Reported in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo) Intent-to-treat population. Number of Patients (%) Placebo Sitagliptin 100 mg once daily Metformin HCl 500 mg/ Metformin HCl 1,000 mg twice daily Data pooled for the patients given the lower and higher doses of metformin. Sitagliptin 50 mg twice daily + Metformin HCl 500 mg/ Metformin HCl 1,000 mg twice daily N = 176 N = 179 N = 364 N = 372 Diarrhea 7 (4) 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 Mellitus 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 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 Reported in Patients with Type 2 Diabetes Mellitus Receiving Sitagliptin and Metformin Number of Patients (%) Trial of Sitagliptin and Metformin in Patients Inadequately Controlled on Diet and Exercise Trial 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 Data pooled for the patients given the lower and higher doses of metformin. 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 Diarrhea 7 (4) 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) 2 (0.5) 8 (2.2) 2 (0.8) 5 (1.1) Abdominal Pain Abdominal discomfort was included in the analysis of abdominal pain in the trial of initial therapy. 4 (2.3) 6 (3.4) 14 (3.8) 11 (3) 9 (3.8) 10 (2.2) Sitagliptin in Combination with Metformin and Glimepiride In a 24-week placebo-controlled trial of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin and glimepiride (sitagliptin, N=116; placebo, N=113), the adverse reactions reported in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia ( see Table 3) and headache (6.9%, 2.7%). Sitagliptin in Combination with Metformin and Rosiglitazone In a placebo-controlled trial of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse reactions reported 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 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 trial of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin and insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction reported in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3). Hypoglycemia In the above trials (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 Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required: Intent-to-treat population. in Placebo-Controlled Clinical Trials of Sitagliptin in Combination with Metformin Coadministered with Glimepiride or Insulin 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) Based on total number of events (i.e., a single patient may have had multiple events). 0.82 0.02 Severe (%) Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure. 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 mellitus 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 mellitus 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 trial 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, trial of patients with type 2 diabetes mellitus 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 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 trials, 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 ZITUVIMET, 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. Skin and subcutaneous tissue disorders: hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome; bullous pemphigoid; Respiratory, thoracic and mediastinal disorders: upper respiratory tract infection; Hepatobiliary disorders: hepatic enzyme elevations; cholestatic, hepatocellular, and mixed hepatocellular liver injury; Gastrointestinal disorders: acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1)]; constipation; vomiting; mouth ulceration; stomatitis; Renal and urinary disorders: worsening renal function, including acute renal failure (sometimes requiring dialysis) and tubulointerstitial nephritis; Musculoskeletal and connective tissue disorders: severe and disabling arthralgia; myalgia; pain in extremity; back pain; pruritus; rhabdomyolysis; Nervous system disorders : headache.

16 HOW SUPPLIED/STORAGE AND HANDLING Tablets supplied as follows: Contents Description How Supplied NDC 50 mg sitagliptin and 500 mg metformin HCl White to off-white, oval shaped, biconvex, film coated tablets debossed with "1786" on one side and plain on the other side. Bottles of 60 tablets with child-resistant closure. NDC 70771-1859-6 Bottles of 180 tablets with child-resistant closure. NDC 70771-1859-8 50 mg sitagliptin and 1,000 mg metformin HCl Reddish brown, oval shaped, biconvex, film coated tablets debossed with "1787" on one side and plain on the other side Bottles of 60 tablets with child-resistant closure. NDC 70771-1860-6 Bottles of 180 tablets with child-resistant closure. NDC 70771-1860-8 Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F), [see USP Controlled Room Temperature]. Protect from moisture.