Alogliptin

1 INDICATIONS AND USAGE Alogliptin 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) ]. Alogliptin 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 ) Limitations of Use: Should not be used in patients with type 1 diabetes. ( 1 ) Limitations of Use Alogliptin tablets should not be used in patients with type 1 diabetes mellitus.

2 DOSAGE AND ADMINISTRATION The recommended dose in patients with normal renal function or mild renal impairment is 25 mg once daily. ( 2.1 ) Can be taken with or without food. ( 2.1 ) Adjust dose if moderate or severe renal impairment or end-stage renal disease (ESRD). ( 2.2 ) Degree of Renal Impairment Creatinine Clearance (mL/min) Recommended Dosing Moderate ≥30 to <60 12.5 mg once daily Severe/ESRD <30 6.25 mg once daily 2.1 Recommended Dosing The recommended dose of alogliptin tablets is 25 mg once daily. Alogliptin tablets may be taken with or without food. Do not split tablets. 2.2 Patients with Renal Impairment No dose adjustment of alogliptin tablets is necessary for patients with mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min). The dose of alogliptin tablets is 12.5 mg once daily for patients with moderate renal impairment (CrCl ≥30 to <60 mL/min). The dose of alogliptin tablets 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). Alogliptin tablets may be administered without regard to the timing of dialysis. Alogliptin tablets have not been studied in patients undergoing peritoneal dialysis [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. Because there is a need for dose adjustment based upon renal function, assessment of renal function is recommended prior to initiation of alogliptin tablets therapy and periodically thereafter.

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) ] The most common adverse reactions (4% or greater incidence) are nasopharyngitis, headache and upper respiratory tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals 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 participated in 14 randomized, double-blind, controlled clinical trials of whom 9052 subjects were treated with alogliptin tablets, 3469 subjects were treated with placebo and 2257 were treated with an active comparator. The mean duration of diabetes 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 alogliptin tablets was 49 weeks with 3348 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 alogliptin tablets 25 mg compared to 75% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse reactions was 6.8% with alogliptin tablets 25 mg compared to 8.4% with placebo or 6.2% with active comparator. Adverse reactions reported in ≥4% of patients treated with alogliptin tablets 25 mg and more frequently than in patients who received placebo are summarized in Table 1 . Table 1. Adverse Reactions Reported in ≥4% Patients Treated with Alogliptin Tablets 25 mg and More Frequently Than in Patients Given Placebo in Pooled Studies Number of Patients (%) Alogliptin Tablets 25 mg Placebo Active Comparator N=6447 N=3469 N=2257 Nasopharyngitis 309 (4.8) 152 (4.4) 113 (5.0) Upper Respiratory Tract Infection 287 (4.5) 121 (3.5) 113 (5.0) Headache 278 (4.3) 101 (2.9) 121 (5.4) Hypoglycemia Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia. In the monotherapy study, the incidence of hypoglycemia was 1.5% in patients treated with alogliptin tablets compared to 1.6% with placebo. The use of alogliptin tablets as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy study comparing alogliptin tablets to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with alogliptin tablets 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 Studies when Alogliptin Tablets Were Used as Add-On Therapy to Glyburide, Insulin, Metformin, Pioglitazone or Compared to Glipizide or Metformin Add-On to Glyburide (26 Weeks) Alogliptin Tablets 25 mg Placebo N=198 N=99 Overall (%) 19 (9.6) 11 (11.1) Severe (%) Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level or loss of consciousness or seizure. 0 1 (1) Add-On to Insulin (± Metformin) (26 Weeks) Alogliptin Tablets 25 mg Placebo N=129 N=129 Overall (%) 35 (27) 31 (24) Severe (%) 1 (0.8) 2 (1.6) Add-On to Metformin (26 Weeks) Alogliptin Tablets 25 mg Placebo N=207 N=104 Overall (%) 0 3 (2.9) Severe (%) 0 0 Add-On to Pioglitazone (± Metformin or Sulfonylurea) (26 Weeks) Alogliptin Tablets 25 mg Placebo N=199 N=97 Overall (%) 14 (7.0) 5 (5.2) Severe (%) 0 1 (1) Compared to Glipizide (52 Weeks) Alogliptin Tablets 25 mg Glipizide N=222 N=219 Overall (%) 12 (5.4) 57 (26) Severe (%) 0 3 (1.4) Compared to Metformin (26 Weeks) Alogliptin Tablets 25 mg Metformin 500 mg twice daily N=112 N=109 Overall (%) 2 (1.8) 2 (1.8) Severe (%) 0 0 Add-On to Metformin Compared to Glipizide (52 Weeks) Alogliptin Tablets 25 mg Glipizide N=877 N=869 Overall (%) 12 (1.4) 207 (23.8) Severe (%) 0 4 (0.5) In the EXAMINE trial, the incidence of investigator reported hypoglycemia was 6.7% in patients receiving alogliptin tablets and 6.5% in patients receiving placebo. Serious adverse reactions of hypoglycemia were reported in 0.8% of patients treated with alogliptin tablets and in 0.6% of patients treated with placebo. Renal Impairment In glycemic control trials in patients with type 2 diabetes, 3.4% of patients treated with alogliptin tablets and 1.3% of patients treated with placebo had renal function adverse reactions. The most commonly reported adverse reactions were renal impairment (0.5% for alogliptin tablets and 0.1% for active comparators or placebo), decreased creatinine clearance (1.6% for alogliptin tablets and 0.5% for active comparators or placebo) and increased blood creatinine (0.5% for alogliptin tablets and 0.3% for active comparators or placebo) [see Use in Specific Populations (8.6) ] . In the EXAMINE trial of high CV risk type 2 diabetes patients, 23% of patients treated with alogliptin tablets and 21% of patients treated with placebo had an investigator reported renal impairment adverse reaction. The most commonly reported adverse reactions were renal impairment (7.7% for alogliptin tablets and 6.7% for placebo), decreased glomerular filtration rate (4.9% for alogliptin tablets and 4.3% for placebo) and decreased renal clearance (2.2% for alogliptin tablets and 1.8% for placebo). Laboratory measures of renal function were also assessed. Estimated glomerular filtration rate decreased by 25% or more in 21.1% of patients treated with alogliptin tablets and 18.7% of patients treated with placebo. Worsening of chronic kidney disease stage was seen in 16.8% of patients treated with alogliptin tablets and in 15.5% of patients treated with placebo. 6.2 Postmarketing Experience The following adverse reactions have been identified during the postmarketing use of alogliptin tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: acute pancreatitis, diarrhea, constipation, nausea, ileus Hepatobiliary disorders: fulminant hepatic failure Immune system disorders: hypersensitivity reactions including anaphylaxis Investigations: hepatic enzyme elevations Musculoskeletal and Connective Tissue Disorders: severe and disabling arthralgia, rhabdomyolysis Renal and urinary disorders: tubulointerstitial nephritis Skin and subcutaneous tissue disorders: angioedema, rash, urticaria and severe cutaneous adverse reactions including Stevens-Johnson syndrome, bullous pemphigoid

12.3 Pharmacokinetics The pharmacokinetics of alogliptin tablets has been studied in healthy subjects and in patients with type 2 diabetes. After administration of single, oral doses up to 800 mg in healthy subjects, the peak plasma alogliptin concentration (median T max ) occurred one to two hours after dosing. At the maximum recommended clinical dose of 25 mg, alogliptin tablets were eliminated with a mean terminal half-life (T 1/2 ) of approximately 21 hours. After multiple-dose administration up to 400 mg for 14 days in patients with type 2 diabetes, accumulation of alogliptin was minimal with an increase in total [e.g., area under the plasma concentration curve (AUC)] and peak (i.e., C max ) alogliptin exposures of 34% and 9%, respectively. Total and peak exposure to alogliptin increased proportionally across single doses and multiple doses of alogliptin ranging from 25 mg to 400 mg. The intersubject coefficient of variation for alogliptin AUC was 17%. The pharmacokinetics of alogliptin tablets were also shown to be similar in healthy subjects and in patients with type 2 diabetes. Absorption The absolute bioavailability of alogliptin tablets is approximately 100%. Administration of alogliptin tablets with a high-fat meal results in no significant change in total and peak exposure to alogliptin. Alogliptin tablets may therefore be administered with or without food. Distribution Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues. Alogliptin is 20% bound to plasma proteins. Metabolism Alogliptin does not undergo extensive metabolism and 60% to 71% of the dose is excreted as unchanged drug in the urine. Two minor metabolites were detected following administration of an oral dose of [ 14 C] alogliptin, N -demethylated, M-I (less than 1% of the parent compound), and N -acetylated alogliptin, M-II (less than 6% of the parent compound). M-I is an active metabolite and is an inhibitor of DPP-4 similar to the parent molecule; M-II does not display any inhibitory activity toward DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin. Alogliptin exists predominantly as the ( R )-enantiomer (more than 99%) and undergoes little or no chiral conversion in vivo to the ( S )-enantiomer. The ( S )-enantiomer is not detectable at the 25 mg dose. Excretion The primary route of elimination of [ 14 C] alogliptin-derived radioactivity occurs via renal excretion (76%) with 13% recovered in the feces, achieving a total recovery of 89% of the administered radioactive dose. The renal clearance of alogliptin (9.6 L/hr) indicates some active renal tubular secretion and systemic clearance was 14.0 L/hr. Special Populations Renal Impairment A single-dose, open-label study was conducted to evaluate the pharmacokinetics of alogliptin 50 mg in patients with chronic renal impairment compared with healthy subjects. In patients with mild renal impairment (creatinine clearance [CrCl] ≥60 to <90 mL/min), an approximate 1.2-fold increase in plasma AUC of alogliptin was observed. Because increases of this magnitude are not considered clinically relevant, dose adjustment for patients with mild renal impairment is not recommended. In patients with moderate renal impairment (CrCl ≥30 to <60 mL/min), an approximate two-fold increase in plasma AUC of alogliptin was observed. To maintain similar systemic exposures of alogliptin tablets to those with normal renal function, the recommended dose is 12.5 mg once daily in patients with moderate renal impairment. In patients with severe renal impairment (CrCl ≥15 to <30 mL/min) and end-stage renal disease (ESRD) (CrCl <15 mL/min or requiring dialysis), an approximate three- and four-fold increase in plasma AUC of alogliptin were observed, respectively. Dialysis removed approximately 7% of the drug during a three-hour dialysis session. Alogliptin tablets may be administered without regard to the timing of the dialysis. To maintain similar systemic exposures of alogliptin tablets to those with normal renal function, the recommended dose is 6.25 mg once daily in patients with severe renal impairment, as well as in patients with ESRD requiring dialysis. Hepatic Impairment Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects. The magnitude of these reductions is not considered to be clinically meaningful. Patients with severe hepatic impairment (Child-Pugh Grade C) have not been studied. Use caution when administering alogliptin tablets to patients with liver disease [see Use in Specific Populations (8.6) and Warnings and Precautions (5.4) ] . Gender No dose adjustment of alogliptin tablets is necessary based on gender. Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Geriatric No dose adjustment of alogliptin tablets is necessary based on age. Age did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Pediatric Studies characterizing the pharmacokinetics of alogliptin in pediatric patients have not been performed. Race No dose adjustment of alogliptin tablets is necessary based on race. Race (White, Black, and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Drug Interactions In Vitro Assessment of Drug Interactions In vitro studies indicate that alogliptin is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4, nor an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant concentrations. In Vivo Assessment of Drug Interactions Effects of Alogliptin on the Pharmacokinetics of Other Drugs In clinical studies, alogliptin did not meaningfully increase the systemic exposure to the following drugs that are metabolized by CYP isozymes or excreted unchanged in urine (Figure 1) . No dose adjustment of alogliptin tablets is recommended based on results of the described pharmacokinetic studies. Figure 1. Effect of Alogliptin on the Pharmacokinetic Exposure to Other Drugs *Warfarin was given once daily at a stable dose in the range of 1 mg to 10 mg. Alogliptin had no significant effect on the prothrombin time (PT) or International Normalized Ratio (INR). **Caffeine (1A2 substrate), tolbutamide (2C9 substrate), dextromethorphan (2D6 substrate), midazolam (3A4 substrate) and fexofenadine (P-gp substrate) were administered as a cocktail. Figure 1 Effects of Other Drugs on the Pharmacokinetics of Alogliptin There are no clinically meaningful changes in the pharmacokinetics of alogliptin when alogliptin tablets are administered concomitantly with the drugs described below (Figure 2) . Figure 2. Effect of Other Drugs on the Pharmacokinetic Exposure of Alogliptin Figure 2