Nesina

1 INDICATIONS AND USAGE NESINA ® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. NESINA is 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 ) Limitations of Use: Should not be used in patients with type 1 diabetes mellitus. ( 1 ) Limitations of Use NESINA is not recommended for use in patients with type 1 diabetes mellitus.

2 DOSAGE AND ADMINISTRATION The recommended dosage in patients with normal renal function or mild renal impairment is 25 mg orally once daily. ( 2.1 ) Can be taken with or without food. ( 2.1 ) Adjust dosage if moderate or severe renal impairment or end-stage renal disease (ESRD). ( 2.2 ) Degree of Renal Impairment Creatinine Clearance (mL/min) Recommended Dosage Moderate ≥30 to <60 12.5 mg once daily Severe/ESRD <30 6.25 mg once daily 2.1 Recommended Dosage The recommended dosage of NESINA is 25 mg taken orally once daily. Do not split tablets. NESINA may be taken with or without food [see Clinical Pharmacology (12.3) ] . Instruct patients if a dose is missed, not to double their next dose. 2.2 Patients with Renal Impairment Assess renal function prior to initiation of NESINA and periodically thereafter [see Use in Specific Populations (8.6) ] . No dose adjustment of NESINA is necessary for patients with mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min). The dose of NESINA is 12.5 mg once daily for patients with moderate renal impairment (CrCl ≥30 to <60 mL/min). The dose of NESINA is 6.25 mg once daily for patients with severe renal impairment (CrCl ≥15 to <30 mL/min) or with end-stage renal disease (ESRD) (CrCl <15 mL/min or requiring hemodialysis). NESINA may be administered without regard to the timing of dialysis. NESINA has not been studied in patients undergoing peritoneal dialysis [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] .

3 DOSAGE FORMS AND STRENGTHS 25 mg tablets are light red, oval, biconvex, film-coated, with "TAK ALG-25" printed on one side. 12.5 mg tablets are yellow, oval, biconvex, film-coated, with "TAK ALG-12.5" printed on one side. 6.25 mg tablets are light pink, oval, biconvex, film-coated, with "TAK ALG-6.25" printed on one side. Tablets: 25 mg, 12.5 mg and 6.25 mg ( 3 )

4 CONTRAINDICATIONS NESINA is contraindicated in patients with a history of serious hypersensitivity to alogliptin or any of the excipients in NESINA. Reactions such as anaphylaxis, angioedema and severe cutaneous adverse reactions have been reported [see Warnings and Precautions (5.3) , Adverse Reactions (6.2) ] . History of serious hypersensitivity to alogliptin or any of the excipients in NESINA. ( 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) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Hepatic Effects [see Warnings and Precautions (5.4) ] Severe and Disabling Arthralgia [see Warnings and Precautions (5.6) ] Bullous Pemphigoid [see Warnings and Precautions (5.7) ] Most common adverse reactions (incidence ≥4%) are nasopharyngitis, headache and upper respiratory tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-877-TAKEDA-7 (1-877-825-3327) 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. A total of 14,778 patients with type 2 diabetes mellitus participated in 14 randomized, double-blind, controlled clinical trials of whom 9,052 subjects were treated with NESINA, 3,469 subjects were treated with placebo and 2,257 were treated with an active comparator. The racial distribution of patients exposed to trial medication was 71% White, 17% Asian, 6% Black or African American, 2% American Indian or Alaska Native, 0% Native Hawaiian/Other Pacific Islander and 5% Multiracial or other racial groups. The ethnic distribution was 30% Hispanic or Latino and 70% was not Hispanic or Latino. The mean duration of diabetes mellitus was seven years, the mean body mass index (BMI) was 31 kg/m 2 (49% of patients had a BMI ≥30 kg/m 2 ), and the mean age was 58 years (26% of patients ≥65 years of age). The mean exposure to NESINA was 49 weeks with 3,348 subjects treated for more than one year. In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse reactions was 73% in patients treated with NESINA 25 mg compared to 75% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse reactions was 6.8% with NESINA 25 mg compared to 8.4% with placebo or 6.2% with active comparator. Adverse reactions reported in ≥4% of adult patients treated with NESINA 25 mg and more frequently than in patients who received placebo are summarized in Table 1. Table 1. Adverse Reactions Reported in ≥4% of Adult Patients with Type 2 Diabetes Mellitus Treated with NESINA 25 mg and More Frequently Than in Patients Given Placebo in Pooled Trials Number of Patients (%) NESINA 25 mg Placebo Active Comparator N=6447 N=3469 N=2257 Nasopharyngitis 309 (5) 152 (4) 113 (5) Upper Respiratory Tract Infection 287 (4) 121 (4) 113 (5) Headache 278 (4) 101 (3) 121 (5) Hypoglycemia Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia. In the monotherapy trial, the incidence of hypoglycemia was 1.5% in patients treated with NESINA compared to 1.6% with placebo. The use of NESINA as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy trial comparing NESINA to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with NESINA compared to 26% with glipizide (Table 2) . Table 2. Incidence and Rate of Hypoglycemia Adverse reactions of hypoglycemia were based on all reports of symptomatic and asymptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population in Placebo and Active-Controlled Trials in Adults with Type 2 Diabetes Mellitus when NESINA Was Used as Add-On Therapy to Glyburide, Insulin, Metformin, Pioglitazone or Compared to Glipizide or Metformin Add-On to Glyburide (26 Weeks) NESINA 25 mg Placebo N=198 N=99 Overall (%) 19 (10) 11 (11) Severe (%) Severe events of hypo …

7 DRUG INTERACTIONS 7.1 Insulin Secretagogues and Insulin Insulin and insulin secretagogues are known to cause hypoglycemia. Coadministration of NESINA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue and insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.5) ] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited data with NESINA in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations ] . No adverse developmental effects were observed when alogliptin was administered to pregnant rats and rabbits during organogenesis at exposures 180- and 149-times the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC) [see Data ] . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes mellitus with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >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 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Animal Data Alogliptin administered to pregnant rabbits and rats during the period of organogenesis did not cause adverse developmental effects at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times, the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC). Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats. No adverse developmental outcomes were observed in offspring when alogliptin was administered to pregnant rats during gestation and lactation at doses up to 250 mg/kg (~95 times the 25 mg clinical dose, based on AUC). 8.2 Lactation Risk Summary There is no information regarding the presence of alogliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Alogliptin is present in rat milk: however, due to species specific differences in lactation physiology, animal lactation data may not reliably predict levels in human milk . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for NESINA and any potential adverse effects on the breastfed infant from NESINA or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of NESINA have not been established in pediatric patients. Effectiveness of NESINA was not demonstrated in a 52 week, randomized, double-blind, placebo-controlled trial (NCT02856113) in 151 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus. 8.5 Geriatric Use Of the total number of patients (N=9052) in clinical safety and efficacy trials treated with NESINA, 2,257 (24.9%) patients were 65 years and older and 386 (4.3%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. 8.6 Renal Impairment A total of 602 adult patients with moderate renal impairment (eGFR ≥30 and <60 mL/min/1.73 m 2 ) and 4 patients with severe renal impairment/end-stage renal disease (eGFR <30 mL/min/1.73 m 2 or <15 mL/min/1.73 m 2 , respectively) at baseline were treated with NESINA in clinical trials in patients with type 2 diabetes mellitus. In the EXAMINE trial of high CV risk type 2 diabetes mellitus patients, 694 patients had moderate renal impairment and 78 patients had severe renal impairment or end-stage renal disease at baseline. The recommended dose is 12.5 mg once daily in patients with moderate renal impairment and 6.25 mg once daily in patients with severe renal impai …

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. Alogliptin is a 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. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.

11 DESCRIPTION NESINA tablets contain the active ingredient alogliptin, which is a selective, orally bioavailable inhibitor of the enzymatic activity of DPP-4. Chemically, alogliptin is prepared as a benzoate salt, which is identified as 2-({6-[(3 R )-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2 H )-yl}methyl)benzonitrile monobenzoate. It has a molecular formula of C 18 H 21 N 5 O 2 ∙C 7 H 6 O 2 and a molecular weight of 461.51 daltons. The structural formula is: Alogliptin benzoate is a white to off-white crystalline powder containing one asymmetric carbon in the aminopiperidine moiety. It is soluble in dimethylsulfoxide, sparingly soluble in water and methanol, slightly soluble in ethanol and very slightly soluble in octanol and isopropyl acetate. Each NESINA tablet contains 34 mg, 17 mg or 8.5 mg alogliptin benzoate, which is equivalent to 25 mg, 12.5 mg or 6.25 mg, respectively, of alogliptin and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, mannitol, and microcrystalline cellulose. In addition, the film coating contains the following inactive ingredients: ferric oxide (red or yellow), hypromellose, polyethylene glycol, and titanium dioxide and is marked with printing ink (Gray F1). Chemical Structure

10 OVERDOSAGE In the event of an overdose, it is reasonable to institute the necessary clinical monitoring and supportive therapy as dictated by the patient's clinical status. Per clinical judgment, it may be reasonable to initiate removal of unabsorbed material from the gastrointestinal tract. Alogliptin is minimally dialyzable; over a three-hour hemodialysis session, approximately 7% of the drug was removed. Therefore, hemodialysis is unlikely to be beneficial in an overdose situation. It is not known if NESINA is dialyzable by peritoneal dialysis. In the event of an overdose, contact the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING NESINA tablets are available as film-coated tablets containing 25 mg, 12.5 mg or 6.25 mg of alogliptin as follows: 25 mg tablet: light red, oval, biconvex, film-coated, with "TAK ALG-25" printed on one side, available in: NDC 64764-250-30 Bottles of 30 tablets NDC 64764-250-90 Bottles of 90 tablets NDC 64764-250-50 Bottles of 500 tablets 12.5 mg tablet: yellow, oval, biconvex, film-coated, with "TAK ALG-12.5" printed on one side, available in: NDC 64764-125-30 Bottles of 30 tablets NDC 64764-125-90 Bottles of 90 tablets NDC 64764-125-50 Bottles of 500 tablets 6.25 mg tablet: light pink, oval, biconvex, film-coated, with "TAK ALG-6.25" printed on one side, available in: NDC 64764-625-30 Bottles of 30 tablets NDC 64764-625-90 Bottles of 90 tablets Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].