Alogliptin

1 INDICATIONS AND USAGE 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. ( 1.1 , 14 ) Important Limitations of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis. ( 1.1 ) 1.1 Monotherapy and Combination Therapy 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) ]. Important Limitations of Use Alogliptin tablets are not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

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. 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.

5 WARNINGS AND PRECAUTIONS Acute pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue alogliptin tablets. ( 5.1 ) Heart failure: Consider the risks and benefits of alogliptin tablets prior to initiating treatment in patients at risk for heart failure. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of alogliptin tablets ( 5.2 ). Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin tablets such as anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. In such cases, promptly discontinue alogliptin tablets, assess for other potential causes, institute appropriate monitoring and treatment and initiate alternative treatment for diabetes. ( 5.3 ) Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt alogliptin tablets and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart alogliptin tablets if liver injury is confirmed and no alternative etiology can be found. ( 5.4 ) Hypoglycemia: When an insulin secretagogue (e.g., sulfonylurea) or insulin is used in combination with alogliptin tablets, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. ( 5.5 ) 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. ( 5.6 ) 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 alogliptin tablets. ( 5.7 ) Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with alogliptin tablets or any other antidiabetic drug. ( 5.8 ) 5.1 Pancreatitis Acute pancreatitis has been reported in the postmarketing setting and in randomized clinical trials. In glycemic control trials in patients with type 2 diabetes, acute pancreatitis was reported in 6 (0.2%) patients treated with alogliptin tablets 25 mg and 2 (<0.1%) patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes and high cardiovascular (CV) risk), acute pancreatitis was reported in 10 (0.4%) of patients treated with alogliptin tablets and in 7 (0.3%) of patients treated with placebo. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using alogliptin tablets . After initiation of alogliptin tablets, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, alogliptin tablets should promptly be discontinued and appropriate management should be initiated. 5.2 Heart Failure In the EXAMINE trial which enrolled patients with type 2 diabetes and recent acute coronary syndrome, 106 (3.9%) of patients treated with alogliptin tablets and 89 (3.3%) of patients treated with placebo were hospitalized for congestive heart failure. Consider the risks and benefits of alogliptin tablets prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Patients should be advised of the characteristic symptoms of heart failure and should be instructed to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of alogliptin t…

4 CONTRAINDICATIONS History of a serious hypersensitivity reaction to alogliptin-containing products, such as anaphylaxis, angioedema or severe cutaneous adverse reactions. History of a serious hypersensitivity reaction to alogliptin-containing products, such as anaphylaxis, angioedema or severe cutaneous adverse reactions. ( 4 )

7 DRUG INTERACTIONS Alogliptin tablets are primarily renally excreted. Cytochrome (CYP) P450-related metabolism is negligible. No significant drug-drug interactions were observed with the CYP-substrates or inhibitors tested or with renally excreted drugs [see Clinical Pharmacology (12.3) ].

8.1 Pregnancy Risk Summary Limited data with alogliptin 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 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 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 in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes 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).

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 (…