sitagliptin and metformin hydrochloride

1 INDICATIONS AND USAGE Sitagliptin and metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Sitagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with type 1 diabetes mellitus. Sitagliptin and metformin hydrochloride extended-release tablets have not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using sitagliptin and metformin hydrochloride extended-release tablets [see Warnings and Precautions ( 5.2 )]. Sitagliptin and metformin hydrochloride extended-release tablets are 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: Not for the treatment of type 1 diabetes mellitus. ( 1 ) Has not been studied in patients with a history of pancreatitis. ( 1 )

2 DOSAGE AND ADMINISTRATION Take sitagliptin and metformin hydrochloride extended-release tablets orally once daily with a meal. Patients taking two sitagliptin and metformin hydrochloride extended-release tablets should take the tablets together. ( 2.1 ) Individualize the dosage of sitagliptin and metformin hydrochloride extended-release tablets 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 hydrochloride extended-release. ( 2.1 ) The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin hydrochloride once 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 100 mg and the dose of metformin already being taken once daily. For patients taking metformin hydrochloride 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of sitagliptin and metformin hydrochloride extended-release tablets are two 50 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets once daily. ( 2.1 ) Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin immediate-release or sitagliptin and metformin extended-release and sitagliptin and metformin hydrochloride extended-release tablets. ( 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 . Sitagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 . Limit dose of sitagliptin to 50 mg once daily if eGFR falls below 45 mL/min/1.73 m 2 . Sitagliptin and metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.3 ) 2.1 Recommended Dosage and Administration Take sitagliptin and metformin hydrochloride extended-release tablets orally once daily with a meal. Patients taking two sitagliptin and metformin hydrochloride extended-release tablets should take the two tablets together once daily. Individualize the dosage of sitagliptin and metformin hydrochloride extended-release tablets 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) extended-release. The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin hydrochloride 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 hydrochloride immediate-release 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of sitagliptin and metformin hydrochloride extended-release tablets are two 50 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets taken together once daily. Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin hydrochloride immediate-release or sitagliptin and metformin extended-release and sitagliptin and metformin hydrochloride extended-release tablets. Do not split, crush or chew sitagliptin and metformin hydrochloride extended-release tablets . 2.2 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of sitagliptin and metformin hydrochloride extended-release tablets and periodically thereafter. Sitagliptin and metformin hydrochloride extended-rele …

3 DOSAGE FORMS AND STRENGTHS Tablets: Sitagliptin 100 mg and metformin hydrochloride 1,000 mg extended-release tablets are reddish brown to brown colored, oval shaped, film-coated tablets debossed with "1806" on one side and plain on the other side. Sitagliptin 50 mg and metformin hydrochloride 500 mg extended-release tablets are light orange to beige colored, oval shaped, film-coated tablets debossed with "1804" on one side and plain on the other side. Sitagliptin 50 mg and metformin hydrochloride 1,000 mg extended-release tablets are yellow to beige colored, oval shaped, film-coated tablets debossed with "1805" on one side and plain on the other side. Sitagliptin and metformin hydrochloride extended-release Tablets: sitagliptin 100 mg and metformin hydrochloride 1,000 mg extended-release sitagliptin 50 mg and metformin hydrochloride 500 mg extended-release sitagliptin 50 mg and metformin hydrochloride 1,000 mg extended-release ( 3 )

4 CONTRAINDICATIONS Sitagliptin and metformin hydrochloride extended-release tablets are 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. A history of a serious hypersensitivity reaction to sitagliptin, metformin, or any of the excipients in sitagliptin and metformin hydrochloride extended-release tablets. Serious hypersensitivity reactions including anaphylaxis or angioedema have been reported [see Warnings and Precautions ( 5.7 ) and Adverse Reactions ( 6.2 )]. 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 sitagliptin and metformin hydrochloride extended-release tablets, sitagliptin, or metformin, such as anaphylaxis or angioedema) ( 4 )

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 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 )] 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 Immediate-Release 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 immediate-release were coadministered to patients with type 2 diabetes mellitus inadequately controlled on diet and exercise. Table 1 Sitagliptin and Metformin Immediate-Release 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. † Data pooled for the patients given the lower and higher doses of metformin. Number of Patients (%) Placebo Sitagliptin 100 mg once daily Metformin hydrochloride Immediate-Release 500 mg or 1,000 mg twice daily † Sitagliptin 50 mg twice daily + Metformin hydrochloride Immediate-Release 500 mg or 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 Immediate-Release Alone In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin immediate-release regimen, there were no adverse reactions reported 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 immediate-release, 1.9%; placebo and metformin immediate-release, 2.5%). Gastrointestinal Adverse Reactions The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin immediate-release were similar to those reported for patients treated with metformin immediate-release alone. See Table 2. Table 2 Pre-selected Gastrointestinal Adverse Reactions Reported in Patients with Type 2 Diabetes Mellitus Receiving Sitagliptin and Metformin Immediate-Release * 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 trial of initial therapy. Number of Patients (%) Trial of Sitagliptin and Metformin Immediate-Release in Patients Inadequately Controlled on Diet and Exer …

7 DRUG INTERACTIONS Table 4 presents clinically significant drug interactions with sitagliptin and metformin hydrochloride extended-release tablets: Table 4 Clinically Significant Drug Interactions with Sitagliptin and Metformin Hydrochloride Extended-Release Tablets Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with sitagliptin and metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide. Drugs that Reduce Metformin Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT 2 ] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology ( 12.3 )] . Intervention: Consider the benefits and risks of concomitant use with sitagliptin and metformin hydrochloride extended-release tablets. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine. Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention: Warn patients against alcohol intake while receiving sitagliptin and metformin hydrochloride extended-release tablets. Insulin Secretagogues or Insulin Clinical Impact: Coadministration of sitagliptin and metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. Intervention: Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Intervention: When such drugs are administered to a patient receiving sitagliptin and metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving sitagliptin and metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia. Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. ( 7 ) Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. ( 7 ) Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. ( 7 )

8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. ( 8.3 ) Geriatric Use: Assess renal function more frequently. ( 8.5 ) Hepatic Impairment: Avoid use in patients with hepatic impairment. ( 8.7 ) 8.1 Pregnancy Risk Summary The limited available data with sitagliptin and metformin hydrochloride extended-release tablets in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data] . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations] . No adverse developmental effects were observed when sitagliptin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 30-times and 20-times, respectively, the 100 mg clinical dose, based on AUC. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during organogenesis at doses up to 2- and 6-times, respectively, a 2,000 mg clinical dose, based on body surface area [see Data] . The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a hemoglobin A1c (A1c) >7% and has been reported to be as high as 20 to 25% in women with a A1C >10%. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies do not report a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Sitagliptin and Metformin No animal reproduction studies were conducted with the coadministration of sitagliptin and metformin. Sitagliptin In embryo-fetal development studies, sitagliptin administered to pregnant rats and rabbits during organogenesis (gestation day 6 to 20) did not adversely affect developmental outcomes at oral doses up to 250 mg/kg (30-times the 100 mg clinical dose) and 125 mg/kg (20-times the 100 mg clinical dose), respectively, based on AUC. Higher doses in rats associated with maternal toxicity increased the incidence of rib malformations in offspring at 1,000 mg/kg, or approximately 100-times the clinical dose, based on AUC. Placental transfer of sitagliptin was observed in pregnant rats and rabbits. Sitagliptin administered to female rats from gestation day 6 to lactation day 21 caused no functional or behavioral toxicity in offspring of rats at doses up to 1,000 mg/kg. Metformin Metformin did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2,000 mg clinical dose based on body surface area (mg/m 2 ) for rats and rabbits, respectively. 8.2 Lactation Risk Summary There is no information regarding the presence of sitagliptin and metformin hydrochloride in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human …

12.1 Mechanism of Action Sitagliptin and Metformin Hydrochloride Extended-Release Tablets Sitagliptin and metformin hydrochloride extended-release tablets combine two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in adults with type 2 diabetes mellitus: sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin extended-release, a member of the biguanide class. Sitagliptin Sitagliptin is a DPP-4 inhibitor, which exerts its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses. Metformin Metformin is a biguanide that improves glycemic control in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

11 DESCRIPTION Sitagliptin and metformin hydrochloride extended-release tablets for oral use contain two antihyperglycemic medications: sitagliptin and metformin extended-release. Sitagliptin Sitagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Sitagliptin phosphatedrug substance is used to manufacture sitagliptin and metformin hydrochloride extended-release tablets. Sitagliptin phosphate is described chemically as 7-[( R )-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3- a ]pyrazine monophosphate with an molecular formula of C 16 H 15 F 6 N 5 O•H 3 PO 4 and a molecular weight of 505.31. The structural formula is: Sitagliptin phosphate is a white to off-white, crystalline powder and slightly hygroscopic in nature. It is soluble in water, very slightly soluble in anhydrous ethanol and practically insoluble in n-heptane. Metformin Metformin hydrochloride, USP (Imidodicarbonimidic diamide, N , N -dimethyl-, monohydrochloride) is a white crystalline powder with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.6. Metformin hydrochloride, USP is freely soluble in water, slightly soluble in alcohol and is practically insoluble in acetone, and in methylene chloride. The pK a of metformin hydrochloride, USP is 12.1. The pH of 10 % solution of metformin hydrochloride, USP in purified water is 6.89 ( ̴ 7.0), at the temperature 25°C. The structural formula is as shown: Sitagliptin and Metformin Hydrochloride Extended-Release Tablets Sitagliptin and metformin hydrochloride extended-release tablets are available as bi-convex oval, film-coated tablets containing: 62.03 mg sitagliptin phosphate (equivalent to 50 mg sitagliptin) and 500 mg metformin hydrochloride (sitagliptin and metformin hydrochloride extended-release tablets 50/500). 62.03 mg sitagliptin phosphate (equivalent to 50 mg sitagliptin) and 1000 mg metformin hydrochloride (sitagliptin and metformin hydrochloride extended-release tablets 50/1000). 124.06 mg sitagliptin phosphate (equivalent to 100 mg sitagliptin) and 1000 mg metformin hydrochloride (sitagliptin and metformin hydrochloride extended-release tablets 100/1000). All doses of sitagliptin and metformin hydrochloride extended-release tablets contain the following inactive ingredients: colloidal silicon dioxide, hypromellose, kaolin powder, polyethylene glycol, povidone, propyl gallate, sodium stearyl fumarate. In addition, 50 mg/500 mg tablet contains microcrystalline cellulose. In addition, the film coating for all doses contains the following inactive ingredients: FD&C blue #2/Indigo carmine aluminum lake, carnauba wax, hydroxypropyl cellulose, hypromellose, titanium dioxide. The sitagliptin and metformin hydrochloride extended-release 50 mg/500 mg and 50 mg/1000 mg tablets film coating also contain the inactive ingredient iron oxide yellow. structure1 structure2

10 OVERDOSAGE In the event of overdose with sitagliptin and metformin hydrochloride extended-release tablets, consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Employ supportive measures dictated by the patient's clinical status. Per clinical judgement, consider removal of unabsorbed material from the gastrointestinal tract, and clinical monitoring (including obtaining an ECG). Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis. Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)] . Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

16 HOW SUPPLIED/STORAGE AND HANDLING Tablets supplied as follows: Contents Description How Supplied NDC 50 mg sitagliptin and 500 mg metformin hydrochloride extended-release tablets Light orange to beige colored, oval shaped, film-coated tablets debossed with "1804" on one side and plain on the other side. Bottles of 60 tablets with child-resistant closure NDC 70710-2036-6 50 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets Yellow to beige colored, oval shaped, film-coated tablets debossed with "1805" on one side and plain on the other side. Bottles of 60 tablets with child-resistant closure NDC 70710-2037-6 100 mg sitagliptin and 1,000 mg metformin hydrochloride extended-release tablets Reddish brown to brown colored, oval shaped, film-coated tablets debossed with "1806" on one side and plain on the other side. Bottles of 30 tablets with child-resistant closure NDC 70710-2038-3 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in a dry place with cap tightly closed. Keep sitagliptin and metformin hydrochloride extended-release tablets in the original container to protect it from moisture. Use sitagliptin and metformin hydrochloride extended-release tablets within 1 month of opening the bottle.