Saxagliptin

5 WARNINGS AND PRECAUTIONS • Pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue saxagliptin tablets. ( 5.1 ) • Heart Failure: Consider the risks and benefits of saxagliptin tablets in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. ( 5.2 ) • Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues: Consider a lower dosage of insulin or insulin secretagogue when used in combination with saxagliptin tablets. ( 5.3 ) • Hypersensitivity-Related Events: There have been postmarketing reports of serious hypersensitivity reactions such as anaphylaxis, angioedema, and exfoliative skin conditions. If hypersensitivity reactions occur, discontinue saxagliptin tablets, treat promptly, and monitor until signs and symptoms resolve. ( 5.4 ) • Arthralgia : 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. ( 5.5 ) • Bullous Pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue saxagliptin tablets. ( 5.6 ) 5.1 Pancreatitis There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin tablets. In a cardiovascular outcomes trial enrolling participants with established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (SAVOR trial), cases of definite acute pancreatitis were confirmed in 17 of 8240 (0.2%) patients receiving saxagliptin tablets compared to 9 of 8173 (0.1%) receiving placebo. Preexisting risk factors for pancreatitis were identified in 88% (15/17) of those patients receiving saxagliptin tablets and in 100% (9/9) of those patients receiving placebo. After initiation of saxagliptin tablets, observe patients for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue saxagliptin tablets and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using saxagliptin tablets. 5.2 Heart Failure In a cardiovascular outcomes trial enrolling participants with established ASCVD or multiple risk factors for ASCVD (SAVOR trial), more patients randomized to saxagliptin tablets (289/8280, 3.5%) were hospitalized for heart failure compared to patients randomized to placebo (228/8212, 2.8%). In a time-to-first-event analysis the risk of hospitalization for heart failure was higher in the saxagliptin tablets group (estimated Hazard Ratio: 1.27; 95% CI: 1.07, 1.51). Patients with a prior history of heart failure and patients with renal impairment had a higher risk for hospitalization for heart failure, irrespective of treatment assignment. Consider the risks and benefits of saxagliptin tablets prior to initiating treatment in patients at a higher risk for heart failure. Observe 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 saxagliptin tablets. 5.3 Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues When saxagliptin tablets were used in combination with insulin or an insulin secretagogue, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with insulin or an insulin secretagogue [ see Adverse Reactions (6.1) ]. Therefore, a lower dosage of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with saxagliptin tablets [ see Drug Interactions (7.2) ]. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.4 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with saxagliptin tablets. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with saxagliptin tablets, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue saxagliptin tablets, assess for other potential causes for the event, and institute alternative treatment for diabetes [ see Adverse Reactions (6.2) ]. Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with saxagliptin tablets. 5.5 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. 5.6 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 saxagliptin tablets. If bullous pemphigoid is suspected, saxagliptin tablets should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

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 tablets and a thiazolidinedione (TZD) than in patients treated with the combination of placebo and TZD. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 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 tablets and a mean duration of exposure to saxagliptin tablets 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, 10.5% other races 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 ≥ 60 mL/min/1.73 m 2 ) in 91% of these patients. Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of saxagliptin tablets. These adverse reactions occurred more commonly on saxagliptin tablets than on placebo and occurred in at least 5% of patients treated with saxagliptin tablets. Table 1: Adverse Reactions in Placebo-Controlled Trials The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin hydrochloride (HCl), thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue. Reported in ≥ 5% of Patients Treated with Saxagliptin Tablets 5 mg and More Commonly than in Patients Treated with Placebo % of Patients Saxagliptin Tablets 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 tablets 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 tablets 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for saxagliptin tablets 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 tablets 2.5 mg and saxagliptin tablets 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 1.0 and 0.6 per 100 patient-years, respectively, for saxagliptin tablets (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The 10 mg dosage is not an approved dosage. The incidence rate of fracture events in patients who received saxagliptin tablets did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of saxagliptin tablets on bone. An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to saxagliptin tablets is not known. Discontinuation of therapy due to adverse reactions occurred in 2.2%, 3.3%, and 1.8% of patients receiving saxagliptin tablets 2.5 mg, saxagliptin tablets 5 mg, and placebo, respectively. The most common adverse reactions (reported in at least 2 patients treated with saxagliptin tablets 2.5 mg or at least 2 patients treated with saxagliptin tablets 5 mg) associated with premature discontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). Adverse Reactions with Concomitant Use with Insulin In the add-on to insulin trial [ see Clinical Studies (14.1) ], the incidence of adverse reactions, including serious adverse reactions and discontinuations due to adverse reactions, was similar between saxagliptin tablets and placebo, except for confirmed hypoglycemia [ see Adverse Reactions (6.1) ]. Hypoglycemia Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia. In the add-on to glyburide trial, the overall incidence of reported hypoglycemia was higher for saxagliptin tablets 2.5 mg and saxagliptin tablets 5 mg (13.3% and 14.6%) versus placebo (10.1%). The incidence of confirmed hypoglycemia in this trial, defined as symptoms of hypoglycemia accompanied by a fingerstick glucose value of ≤ 50 mg/dL, was 2.4% and 0.8% for saxagliptin tablets 2.5 mg and saxagliptin tablets 5 mg and 0.7% for placebo [ see Warnings and Precautions (5.3) ]. The incidence of reported hypoglycemia for saxagliptin tablets 2.5 mg and saxagliptin tablets 5 mg versus placebo given as monotherapy was 4% and 5.6% versus 4.1%, respectively, 7.8% and 5.8% versus 5% given as add-on therapy to metformin HCl, and 4.1% and 2.7% versus 3.8% given as add-on therapy to TZD. The incidence of reported hypoglycemia was 3.4% in treatment-naive patients given saxagliptin tablets 5 mg plus metformin HCl and 4% in patients given metformin HCl alone. In the active-controlled trial comparing add-on therapy with saxagliptin tablets 5 mg to glipizide in patients inadequately controlled on metformin HCl alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with saxagliptin tablets 5 mg versus 36.3% (750 events in 156 patients) with glipizide. Confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤ 50 mg/dL) was reported in none of the saxagliptin tablet-treated patients and in 35 glipizide-treated patients (8.1%) (p 6 mg/dL), were reported in 5.8% (483/8280) of saxagliptin tablet-treated patients and 5.1% (422/8212) of placebo-treated patients. The most frequently reported adverse reactions included renal impairment (2.1% vs. 1.9%), acute renal failure (1.4% vs. 1.2%), and renal failure (0.8% vs. 0.9%), in the saxagliptin tablets versus placebo groups, respectively. From baseline to the end of treatment, there was a mean decrease in eGFR of 2.5 mL/min/1.73 m 2 for saxagliptin tablet-treated patients and a mean decrease of 2.4 mL/min/1.73 m 2 for placebo-treated patients. More patients randomized to saxagliptin tablets (421/5227, 8.1%) compared to patients randomized to placebo (344/5073, 6.8%) had downward shifts in eGFR from > 50 mL/min/1.73 m 2 (i.e., normal or mild renal impairment) to ≤ 50 mL/min/1.73 m 2 (i.e., moderate or severe renal impairment). The proportions of patients with renal adverse reactions increased with worsening baseline renal function and increased age, regardless of treatment assignment. Infections In the unblinded, controlled, clinical trial database for saxagliptin tablets to date, there have been 6 (0.12%) reports of tuberculosis among the 4959 saxagliptin tablet-treated patients (1.1 per 1000 patient-years) compared to no reports of tuberculosis among the 2868 comparator-treated patients. Two of these six cases were confirmed with laboratory testing. The remaining cases had limited information or had presumptive diagnoses of tuberculosis. None of the six cases occurred in the United States or in Western Europe. One case occurred in Canada in a patient originally from Indonesia who had recently visited Indonesia. The duration of treatment with saxagliptin tablets until report of tuberculosis ranged from 144 to 929 days. Post-treatment lymphocyte counts were consistently within the reference range for four cases. One patient had lymphopenia prior to initiation of saxagliptin tablets that remained stable throughout saxagliptin tablet treatment. The final patient had an isolated lymphocyte count below normal approximately four months prior to the report of tuberculosis. There have been no spontaneous reports of tuberculosis associated with saxagliptin tablet use. Causality has not been estimated and there are too few cases to date to determine whether tuberculosis is related to saxagliptin tablet use. There has been one case of a potential opportunistic infection in the unblinded, controlled clinical trial database to date in a saxagliptin tablet-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of saxagliptin tablet therapy. There have been no spontaneous reports of opportunistic infections associated with saxagliptin tablet use. Vital Signs No clinically meaningful changes in vital signs have been observed in patients treated with saxagliptin tablets. Laboratory Tests Absolute Lymphocyte Counts There was a dose-related mean decrease in absolute lymphocyte count observed with saxagliptin tablets. From a baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with saxagliptin tablets 5 mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in a pooled analysis of five placebo-controlled clinical trials. Similar effects were observed when saxagliptin tablets 5 mg were given in initial combination with metformin HCl compared to metformin HCl alone. There was no difference observed for saxagliptin tablets 2.5 mg relative to placebo. The proportion of patients who were reported to have a lymphocyte count ≤ 750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin tablets 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to saxagliptin tablets although some patients had recurrent decreases upon rechallenge that led to discontinuation of saxagliptin tablets. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The 10 mg dosage is not an approved dosage. In the SAVOR trial mean decreases of approximately 84 cells/microL with saxagliptin tablets relative to placebo was observed. The proportion of patients who experienced a decrease in lymphocyte counts to a count of ≤ 750 cells/microL was 1.6% (136/8280) and 1.0% (78/8212) on saxagliptin tablets and placebo, respectively. The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of saxagliptin tablets on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of saxagliptin tablets. 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. • Gastrointestinal Disorders: Pancreatitis • Immune System Disorders: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions • Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, Severe and disabling arthralgia • Skin and Subcutaneous Tissue Disorders: Bullous pemphigoid

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 Pharmacology (12.3) ]. 8.6 Renal Impairment In a 12-week randomized placebo-controlled trial, saxagliptin tablets 2.5 mg were administered orally to 85 patients with moderate (n = 48) or severe (n = 18) renal impairment or end-stage renal disease (ESRD) (n = 19) [ see Clinical Studies (14) ]. The incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between saxagliptin tablets and placebo. The overall incidence of reported hypoglycemia was 20% among patients treated with saxagliptin tablets 2.5 mg and 22% among patients treated with placebo. Four saxagliptin tablet-treated patients (4.7%) and three placebo-treated patients (3.5%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying fingerstick glucose ≤ 50 mg/dL).

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.