SAXAGLIPTIN

1 INDICATIONS AND USAGE Saxagliptin tablets are a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1.1 ) Limitations of use: • Not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. ( 1.2 ) 1.1 Monotherapy and Combination Therapy Saxagliptin tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [ see Clinical Studies ( 14 ) ]. 1.2 Limitation of Use Saxagliptin tablets are not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

1.1 Monotherapy and Combination Therapy Saxagliptin tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [ see Clinical Studies ( 14 ) ].

2 DOSAGE AND ADMINISTRATION • Recommended dosage is 2.5 mg or 5 mg orally once daily taken regardless of meals. ( 2.1 ) • Patients with an eGFR < 45 mL/min/1.73 m 2 (moderate or severe renal impairment, or end-stage renal disease): Recommended dosage is 2.5 mg once daily regardless of meals. ( 2.2 ) • Assess renal function before starting saxagliptin tablets and periodically thereafter. ( 2.2 ) • Limit the dosage of saxagliptin tablets to 2.5 mg daily for patients also taking strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole). ( 2.3 ) 2.1 Recommended Dosage The recommended dosage of saxagliptin tablets is 2.5 mg or 5 mg orally once daily taken regardless of meals. Do not cut, crush, or chew saxagliptin tablets. If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose. 2.2 Dosage in Patients with Renal Impairment Assess renal function prior to initiation of saxagliptin tablets and then as clinically indicated [ see Use in Specific Populations (8.6) ]. The recommended dosage of saxagliptin tablets in patients with an eGFR greater than or equal to 45 mL/minute/1.73 m 2 is the same as the recommended dosage in patients with normal renal function [ see Dosage and Administration (2.1) ]. The dosage of saxagliptin tablets is 2.5 mg orally once daily for patients with eGFR < 45 mL/min/1.73 m 2 [which includes a subset of moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis] [ see Clinical Pharmacology (12.3) and Clinical Studies (14.2) ]. Saxagliptin tablets should be administered following hemodialysis. Saxagliptin tablets have not been studied in patients undergoing peritoneal dialysis. 2.3 Dosage Modification with Concomitant Use of Strong CYP3A4/5 Inhibitors The dosage of saxagliptin tablets is 2.5 mg orally once daily when used concomitantly with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) [ see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ].

3 DOSAGE FORMS AND STRENGTHS Saxagliptin Tablets are available containing 3.075 mg or 6.149 mg of saxagliptin hydrochloride dihydrate equivalent to 2.5 mg or 5 mg of saxagliptin. • The 2.5 mg tablets are yellow, film-coated, round, unscored tablets imprinted with SX1 over M in black ink on one side of the tablet and blank on the other side. • The 5 mg tablets are white to off-white, film-coated, round, unscored tablets imprinted with SX2 over M in black ink on one side of the tablet and blank on the other side. • Tablets: 5 mg and 2.5 mg. ( 3 )

4 CONTRAINDICATIONS Saxagliptin tablets are contraindicated in patients with a history of a serious hypersensitivity reaction to saxagliptin or any of the ingredients in saxagliptin tablets. Reactions such as anaphylaxis, angioedema, or exfoliative skin conditions have been reported with saxagliptin tablets [ see Warnings and Precautions (5.4) and Adverse Reactions (6.2) ]. • History of a serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to saxagliptin or any of the ingredients in saxagliptin tablets. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Pancreatitis [ see Warnings and Precautions (5.1) ] • Heart Failure [ see Warnings and Precautions (5.2) ] • Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues [ see Warnings and Precautions ( 5.3 ) ] • Hypersensitivity Reactions [ see Warnings and Precautions ( 5.4 ) ] • Severe and disabling arthralgia [ see Warnings and Precautions (5.5) ] • Bullous pemphigoid [ see Warnings and Precautions (5.6) ] • Most common adverse reactions (incidence ≥ 5% and more often than placebo) are upper respiratory tract infection, urinary tract infection, and headache. ( 6.1 ) • Peripheral edema was reported more commonly in patients treated with the combination of saxagliptin and a thiazolidinedione (TZD) than in patients treated with the combination of placebo and TZD. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 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. Adverse Reactions in Efficacy Trials 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. Adverse Reactions in Placebo-Controlled Trials in Adults with Type 2 Diabetes Mellitus The data in Table 1 are derived from a pool of 5 placebo-controlled clinical trials [ see Clinical Studies (14) ]. These data shown in the table reflect exposure of 882 patients to saxagliptin and a mean duration of exposure to saxagliptin of 21 weeks. The mean age of these patients was 55 years, 1.4% were 75 years of age or older and 48.4% were male. The population was 67.5% White, 4.6% Black or African American, 17.4% Asian, other races 10.5% and 9.8% were of Hispanic or Latino ethnicity. At baseline the population had type 2 diabetes mellitus for an average of 5.2 years and a mean HbA1c of 8.2%. Baseline estimated renal function was normal or mildly impaired (eGFR ≥ 60mL/min/1.73 m 2 ) in 91% of these patients. Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of saxagliptin. These adverse reactions occurred more commonly on saxagliptin than on placebo and occurred in at least 5% of patients treated with saxagliptin. Table 1: Adverse Reactions in Placebo-Controlled Trials* Reported in ≥ 5% of Patients Treated with Saxagliptin 5 mg and More Commonly than in Patients Treated with Placebo % of Patients Saxagliptin 5 mg N=882 Placebo N=799 Upper respiratory tract infection 7.7 7.6 Urinary tract infection 6.8 6.1 Headache 6.5 5.9 In patients treated with saxagliptin 2.5 mg, headache (6.5%) was the only adverse reaction reported at a rate ≥ 5% and more commonly than in patients treated with placebo. In the add-on to TZD trial, the incidence of peripheral edema was higher for saxagliptin 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for saxagliptin 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema resulted in trial drug discontinuation. Rates of peripheral edema for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1% versus 2.2% given as add-on therapy to metformin HCl, and 2.4% and 1.2% versus 2.2% given as add-on therapy to glyburide. The incidence rate of fractures was 1 and 0.6 per 100 patient-years, respectively, for saxagliptin (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The 10 mg dosage is not an approved dosage. The incide …

7 DRUG INTERACTIONS • Strong CYP3A4/5 inhibitors (e.g., ketoconazole): Coadministration with saxagliptin tablets significantly increases saxagliptin concentrations. Limit saxagliptin tablets dosage to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor. ( 7.1 ) 7.1 Strong Inhibitors of CYP3A4/5 Enzymes Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). The dosage of saxagliptin tablets should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor [ see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ]. 7.2 Insulin or Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. Concomitant use of saxagliptin tablets with insulin or an insulin secretagogue may require lower dosages of insulin or the insulin secretagogue to reduce the risk of hypoglycemia [ see Warnings and Precautions (5.3) ].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited data with saxagliptin tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriages. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [ see Clinical Considerations ]. No adverse developmental effects independent of maternal toxicity were observed when saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis and in pregnant and lactating rats during the pre- and postnatal period [ see Data ]. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with an HbA1c greater than 7 and has been reported to be as high as 20 to 25% in women with an HbA1c greater than 10. The estimated background risk of miscarriage for the indicated population is unknown. 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, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data In embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed in either species at exposures 1503- and 152-times the 5 mg clinical dose in rats and rabbits, respectively, based on AUC. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats. In a prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats administered saxagliptin from gestation day 6 through lactation day 21 at exposures up to 470-times the 5 mg clinical dose, based on AUC. 8.2 Lactation Risk Summary There is no information regarding the presence of saxagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Saxagliptin is present in the milk of lactating rats [ see Data ]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for saxagliptin tablets and any potential adverse effects on the breastfed infant from saxagliptin tablets or from the underlying maternal condition. Data Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations. 8.4 Pediatric Use The safety and effectiveness of saxagliptin tablets as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus have not been established in pediatric patients. Effectiveness of saxagliptin tablets was not demonstrated in a 26-week, placebo-controlled, double-blind randomized clinical trial with a 26-week safety extension (NCT03199053) in 164 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus. 8.5 Geriatric Use In the seven, double-blind, controlled clinical safety and efficacy trials of saxagliptin tablets, a total of 4751 (42.0%) of the 11301 patients randomized to saxagliptin tablets were 65 years and over, and 1210 (10.7%) were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients. Saxagliptin and its active metabolite are eliminated in part by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function [ see Dosage and Administration (2.2) and Clinical Pharmaco …

12.1 Mechanism of Action Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus.

11 DESCRIPTION Saxagliptin is an orally-active inhibitor of the DPP-4 enzyme. Saxagliptin monohydrate is described chemically as (1 S ,3 S ,5 S )-2-[(2 S )-2-Amino-2-(3- hydroxytricyclo[3.3.1.1 3,7 ]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, monohydrate or (1 S ,3 S ,5 S )-2-[(2 S )-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carbonitrile hydrate. The molecular formula is C 18 H 25 N 3 O 2 •H 2 O and the molecular weight is 333.43. The structural formula is: Saxagliptin monohydrate is a white to off-white, non-hygroscopic, crystalline powder. It is sparingly soluble in water at 24°C ± 3°C, slightly soluble in ethyl acetate, and soluble in methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and polyethylene glycol 400 (PEG 400). Each film-coated tablet of saxagliptin for oral use contains either 2.79 mg saxagliptin hydrochloride (anhydrous) equivalent to 2.5 mg saxagliptin or 5.58 mg saxagliptin hydrochloride (anhydrous) equivalent to 5 mg saxagliptin and the following inactive ingredients: ascorbic acid, crospovidone, glyceryl monostearate, hydroxypropyl cellulose, iron oxide yellow, magnesium sterate, mannitol, microcrystalline cellulose, polyvinyl alcohol, sodium lauryl sulphate, talc and titanium dioxide. In addition, the 2.5 mg tablets contain FD&C yellow#5/Tartrazine aluminium lake and iron oxide black. The 5 mg tablets contain FD&C yellow#6/Sunset yellow FCF aluminium lake and iron oxide red. Saxagliptin Monohydrate Chemical Structure

10 OVERDOSAGE In a controlled clinical trial, once-daily, orally-administered saxagliptin tablets in healthy patients at doses up to 400 mg daily for 2 weeks (80-times the MRHD) had no dose-related clinical adverse reactions and no clinically meaningful effect on QTc interval or heart rate. In the event of an overdose, initiate appropriate supportive treatment as dictated by the patient’s clinical status. Saxagliptin and its active metabolite are removed by hemodialysis (23% of dose over 4 hours). Contact the Poison Help Line, (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Saxagliptin Tablets are available containing 3.075 mg or 6.149 mg of saxagliptin hydrochloride dihydrate equivalent to 2.5 mg or 5 mg of saxagliptin. The 2.5 mg tablets are yellow, film-coated, round, unscored tablets imprinted with SX1 over M in black ink on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-4705-93 bottles of 30 tablets NDC 0378-4705-77 bottles of 90 tablets The 5 mg tablets are white to off-white, film-coated, round, unscored tablets imprinted with SX2 over M in black ink on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-4706-93 bottles of 30 tablets NDC 0378-4706-77 bottles of 90 tablets Storage and Handling Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription.