英文药名：Nesina(alogliptin Tablets) 中文药名：阿格列汀片 生产厂家：武田制药北美公司 药品介绍 【通用药名】Alogliptin 阿格列汀 【化学名称】2-[6-[3(R)-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrile benzoate 【结 构 式】 【分 子 式】C25H27N5O4 【分 子 量】461.513 【开发单位】日本Takeda公司 【首次上市】2010年4月获得日本厚生劳动省的上市批准 【性　状】薄膜包衣片剂，不同规格颜色不同（25mg 黄色；12.5mg 淡黄色；6.25mg 淡红色） 【用　途】适用于治疗2型糖尿病 阿格列汀(alogliptin),即苯甲酸阿格列汀,是由日本Takeda公司研发的一种丝氨酸蛋白酶二肽基肽酶Ⅳ(DPP-Ⅳ)抑制剂,于2013年1月获美国FDA批准上市,商品名为Nesina。该药为片剂,用于治疗因糖代谢自身稳定控制功能受损而导致的2型糖尿病. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use NESINA safely and effectively. See full prescribing information for NESINA. NESINA (alogliptin) tablets Initial U.S. Approval: 2013 RECENT MAJOR CHANGES Warnings and Precautions (5.5)                         8/2015 INDICATIONS AND USAGE 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. (1.1, 14) Limitation of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1.2) 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 DOSAGE FORMS AND STRENGTHS Tablets: 25 mg, 12.5 mg and 6.25 mg (3) CONTRAINDICATIONS History of a serious hypersensitivity reaction to alogliptin-containing products, such as anaphylaxis, angioedema or severe cutaneous adverse reactions. (4) WARNINGS AND PRECAUTIONS • Acute pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue NESINA. ( 5.1) • Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with NESINA such as anaphylaxis, angioedema and severe cutaneous adverse reactions. In such cases, promptly discontinue NESINA, assess for other potential causes, institute appropriate monitoring and treatment and initiate alternative treatment for diabetes. ( 5.2) • Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt NESINA and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart NESINA if liver injury is confirmed and no alternative etiology can be found. ( 5.3) • Hypoglycemia: When an insulin secretagogue (e.g., sulfonylurea) or insulin is used in combination with NESINA, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. ( 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) • Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with NESINA or any other antidiabetic drug. ( 5.6) ADVERSE REACTIONS Common adverse reactions (reported in ≥4% of patients treated with NESINA 25 mg and more frequently than in patients who received placebo) 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. See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 8/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Monotherapy and Combination Therapy NESINA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies (14)]. 1.2 Limitation of Use NESINA should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing The recommended dose of NESINA is 25 mg once daily. NESINA may be taken with or without food. 2.2 Patients with Renal Impairment 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 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 NESINA therapy and periodically thereafter. 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. 4 CONTRAINDICATIONS History of a serious hypersensitivity reaction to alogliptin-containing products, such as anaphylaxis, angioedema or severe cutaneous adverse reactions. 5 WARNINGS AND PRECAUTIONS 5.1 Pancreatitis There have been postmarketing reports of acute pancreatitis in patients taking NESINA. After initiation of NESINA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, NESINA should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using NESINA. 5.2 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with NESINA. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue NESINA, 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 with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with NESINA. 5.3 Hepatic Effects There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking NESINA, although some of the reports contain insufficient information necessary to establish the probable cause [see Adverse Reactions (6.2)]. In randomized controlled studies, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were observed: 1.3% in alogliptin-treated patients and 1.5% in all comparator-treated patients. Patients with type 2 diabetes may have fatty liver disease, which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel and assessing the patient before initiating NESINA therapy is recommended. In patients with abnormal liver tests, NESINA should be initiated with caution. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have clinically significant liver enzyme elevations and if abnormal liver tests persist or worsen, NESINA should be interrupted and investigation done to establish the probable cause. NESINA should not be restarted in these patients without another explanation for the liver test abnormalities. 5.4 Use with Medications Known to Cause Hypoglycemia Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with NESINA. 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 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with NESINA or any other antidiabetic drug. 6 ADVERSE REACTIONS 6.1 Clinical Studies 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 clinical practice. Approximately 8500 patients with type 2 diabetes have been treated with NESINA in 14 randomized, double-blind, controlled clinical trials with approximately 2900 subjects randomized to placebo and approximately 2200 to an active comparator. The mean exposure to NESINA was 40 weeks with more than 2400 subjects treated for more than one year. Among these patients, 63% had a history of hypertension, 51% had a history of dyslipidemia, 25% had a history of myocardial infarction, 8% had a history of unstable angina and 7% had a history of congestive heart failure. The mean duration of diabetes was seven years, the mean body mass index (BMI) was 31 kg/m2 (51% of patients had a BMI ≥30 kg/m2), and the mean age was 57 years (24% of patients ≥65 years of age). Two placebo-controlled monotherapy trials of 12 and 26 weeks of duration were conducted in patients treated with NESINA 12.5 mg daily, NESINA 25 mg daily and placebo. Four placebo-controlled add-on combination therapy trials of 26 weeks duration were also conducted: with metformin, with a sulfonylurea, with a thiazolidinedione and with insulin. Four placebo-controlled and one active-controlled trials of 16 weeks up through two years in duration were conducted in combination with metformin, in combination with pioglitazone and with pioglitazone added to a background of metformin therapy. Three active-controlled trials of 52 weeks in duration were conducted in patients treated with pioglitazone and metformin, in combination with metformin and as monotherapy compared to glipizide. In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse events was 66% in patients treated with NESINA 25 mg compared to 62% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse events was 4.7% with NESINA 25 mg compared to 4.5% with placebo or 6.2% with active comparator. Adverse reactions reported in ≥4% of 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% Patients Treated with NESINA 25 mg and More Frequently Than in Patients Given Placebo in Pooled Studies Pancreatitis In the clinical trial program, pancreatitis was reported in 11 of 5902 (0.2%) patients receiving NESINA 25 mg daily compared to five of 5183 (<0.1%) patients receiving all comparators. Hypersensitivity Reactions In a pooled analysis, the overall incidence of hypersensitivity reactions was 0.6% with NESINA 25 mg compared to 0.8% with all comparators. A single event of serum sickness was reported in a patient treated with NESINA 25 mg. 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 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 study 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* in Placebo and Active-Controlled Studies when NESINA Was Used as Add-On Therapy to Glyburide, Insulin, Metformin, Pioglitazone or Compared to Glipizide 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. Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level or loss of consciousness or seizure. Vital Signs No clinically meaningful changes in vital signs or in electrocardiograms were observed in patients treated with NESINA. Laboratory Tests No clinically meaningful changes in hematology, serum chemistry or urinalysis were observed in patients treated with NESINA. 6.2 Postmarketing Experience The following adverse reactions have been identified during the postmarketing use of NESINA. 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. Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, hepatic enzyme elevations, fulminant hepatic failure, severe and disabling arthralgia and acute pancreatitis [see Warnings and Precautions (5.1, 5.2, 5.3, 5.5)]. 7 DRUG INTERACTIONS NESINA is 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B No adequate or well-controlled studies in pregnant women have been conducted with NESINA. Based on animal data, NESINA is not predicted to increase the risk of developmental abnormalities. Because animal reproduction studies are not always predictive of human risk and exposure, NESINA, like other antidiabetic medications, should be used during pregnancy only if clearly needed. Alogliptin administered to pregnant rabbits and rats during the period of organogenesis was not teratogenic at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times, respectively, the clinical dose based on plasma drug exposure (AUC). Doses of alogliptin up to 250 mg/kg (approximately 95 times clinical exposure based on AUC) given to pregnant rats from gestation Day 6 to lactation Day 20 did not harm the developing embryo or adversely affect growth and development of offspring. Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats. 8.3 Nursing Mothers Alogliptin is secreted in the milk of lactating rats in a 2:1 ratio to plasma. It is not known whether alogliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NESINA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of NESINA in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of patients (N=8507) in clinical safety and efficacy studies treated with NESINA, 2064 (24.3%) patients were 65 years and older and 341 (4%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No dose adjustments are required in patients with mild to moderate hepatic impairment (Child-Pugh Grade A and B) based on insignificant change in systemic exposures (e.g., AUC) compared to subjects with normal hepatic function in a pharmacokinetic study. NESINA has not been studied in patients with severe hepatic impairment (Child-Pugh Grade C). Use caution when administering NESINA to patients with liver disease [see Warnings and Precautions (5.3)]. 10 OVERDOSAGE The highest doses of NESINA administered in clinical trials were single doses of 800 mg to healthy subjects and doses of 400 mg once daily for 14 days to patients with type 2 diabetes (equivalent to 32 times and 16 times the maximum recommended clinical dose of 25 mg, respectively). No serious adverse events were observed at these doses. 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. 11 DESCRIPTION NESINA tablets contain the active ingredient alogliptin, which is a selective, orally bioavailable inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (DPP-4). Chemically, alogliptin is prepared as a benzoate salt, which is identified as 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile monobenzoate. It has a molecular formula of C18H21N5O2•C7H6O2 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: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, ferric oxide (red or yellow) and polyethylene glycol, and is marked with printing ink (Gray F1). 12 CLINICAL PHARMACOLOGY 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, 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. 12.2 Pharmacodynamics Single-dose administration of NESINA to healthy subjects resulted in a peak inhibition of DPP-4 within two to three hours after dosing. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Peak and total exposure over 24 hours to active GLP-1 were three- to four-fold greater with NESINA (at doses of 25 to 200 mg) than placebo. In a 16-week, double-blind, placebo-controlled study, NESINA 25 mg demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an eight-hour period following a standardized meal. It is unclear how these findings relate to changes in overall glycemic control in patients with type 2 diabetes mellitus. In this study, NESINA 25 mg demonstrated decreases in two-hour postprandial glucose compared to placebo (-30 mg/dL versus 17 mg/dL, respectively). Multiple-dose administration of alogliptin to patients with type 2 diabetes also resulted in a peak inhibition of DPP-4 within one to two hours and exceeded 93% across all doses (25 mg, 100 mg and 400 mg) after a single dose and after 14 days of once-daily dosing. At these doses of NESINA, inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing. Cardiac Electrophysiology In a randomized, placebo-controlled, four-arm, parallel-group study, 257 subjects were administered either alogliptin 50 mg, alogliptin 400 mg, moxifloxacin 400 mg or placebo once daily for a total of seven days. No increase in QTc was observed with either dose of alogliptin. At the 400 mg dose, peak alogliptin plasma concentrations were 19-fold higher than the peak concentrations following the maximum recommended clinical dose of 25 mg. 12.3 Pharmacokinetics The pharmacokinetics of NESINA 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 Tmax) occurred one to two hours after dosing. At the maximum recommended clinical dose of 25 mg, NESINA was eliminated with a mean terminal half-life (T1/2) 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 (i.e., AUC) and peak (i.e., Cmax) 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 NESINA was also shown to be similar in healthy subjects and in patients with type 2 diabetes. Absorption The absolute bioavailability of NESINA is approximately 100%. Administration of NESINA with a high-fat meal results in no significant change in total and peak exposure to alogliptin. NESINA 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 [14C] alogliptin, N-demethylated, M-I (<1% of the parent compound), and N-acetylated alogliptin, M-II (<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 (>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 [14C] 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. Specific 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 NESINA 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 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. NESINA may be administered without regard to the timing of the dialysis. To maintain similar systemic exposures of NESINA 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 NESINA to patients with liver disease [see Use in Specific Populations (8.6) and Warnings and Precautions (5.3)]. Gender No dose adjustment of NESINA is necessary based on gender. Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Geriatric No dose adjustment of NESINA 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 NESINA 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 NESINA 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. Effects of Other Drugs on the Pharmacokinetics of Alogliptin There are no clinically meaningful changes in the pharmacokinetics of alogliptin when NESINA is administered concomitantly with the drugs described below (Figure 2). Figure 2. Effect of Other Drugs on the Pharmacokinetic Exposure of Alogliptin 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Rats were administered oral doses of 75, 400 and 800 mg/kg alogliptin for two years. No drug-related tumors were observed up to 75 mg/kg or approximately 32 times the maximum recommended clinical dose of 25 mg, based on AUC exposure. At higher doses (approximately 308 times the maximum recommended clinical dose of 25 mg), a combination of thyroid C-cell adenomas and carcinomas increased in male but not female rats. No drug-related tumors were observed in mice after administration of 50, 150 or 300 mg/kg alogliptin for two years, or up to approximately 51 times the maximum recommended clinical dose of 25 mg, based on AUC exposure. Alogliptin was not mutagenic or clastogenic, with and without metabolic activation, in the Ames test with S. typhimurium and E. coli or the cytogenetic assay in mouse lymphoma cells. Alogliptin was negative in the in vivo mouse micronucleus study. In a fertility study in rats, alogliptin had no adverse effects on early embryonic development, mating or fertility at doses up to 500 mg/kg, or approximately 172 times the clinical dose based on plasma drug exposure (AUC). 14 CLINICAL STUDIES NESINA has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione (either alone or in combination with metformin or a sulfonylurea) and insulin (either alone or in combination with metformin). A total of 8673 patients with type 2 diabetes were randomized in 10 double-blind, placebo- or active-controlled clinical safety and efficacy studies conducted to evaluate the effects of NESINA on glycemic control. The racial distribution of patients exposed to study medication was 68% Caucasian, 15% Asian, 7% Black and 9% other racial groups. The ethnic distribution was 30% Hispanic. Patients had an overall mean age of 55 years (range 21 to 80 years). In patients with type 2 diabetes, treatment with NESINA produced clinically meaningful and statistically significant improvements in A1C compared to placebo. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with NESINA appears to be related to the degree of A1C elevation at baseline. NESINA had similar changes from baseline in serum lipids compared to placebo. 14.1 Patients with Inadequate Glycemic Control on Diet and Exercise A total of 1768 patients with type 2 diabetes participated in three double-blind studies to evaluate the efficacy and safety of NESINA in patients with inadequate glycemic control on diet and exercise. All three studies had a four-week, single-blind, placebo run-in period followed by a 26-week randomized treatment period. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment periods received glycemic rescue therapy. In a 26-week, double-blind, placebo-controlled study, a total of 329 patients (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo once daily. Treatment with NESINA 25 mg resulted in statistically significant improvements from baseline in A1C and fasting plasma glucose (FPG) compared to placebo at Week 26 (Table 3). A total of 8% of patients receiving NESINA 25 mg and 30% of those receiving placebo required glycemic rescue therapy. Improvements in A1C were not affected by gender, age or baseline BMI. The mean change in body weight with NESINA was similar to placebo. Table 3. Glycemic Parameters at Week 26 in a Placebo-Controlled Monotherapy Study of NESINA* Intent-to-treat population using last observation on study Least squares means adjusted for treatment, baseline value, geographic region and duration of diabetes p<0.01 compared to placebo In a 26-week, double-blind, active-controlled study, a total of 655 patients (mean baseline A1C = 8.8%) were randomized to receive NESINA 25 mg alone, pioglitazone 30 mg alone, NESINA 12.5 mg with pioglitazone 30 mg or NESINA 25 mg with pioglitazone 30 mg once daily. Coadministration of NESINA 25 mg with pioglitazone 30 mg resulted in statistically significant improvements from baseline in A1C and FPG compared to NESINA 25 mg alone and to pioglitazone 30 mg alone (Table 4). A total of 3% of patients receiving NESINA 25 mg coadministered with pioglitazone 30 mg, 11% of those receiving NESINA 25 mg alone and 6% of those receiving pioglitazone 30 mg alone required glycemic rescue. Improvements in A1C were not affected by gender, age or baseline BMI. The mean increase in body weight was similar between pioglitazone alone and NESINA when coadministered with pioglitazone. Table 4. Glycemic Parameters at Week 26 in an Active-Controlled Study of NESINA, Pioglitazone, and NESINA in Combination with Pioglitazone* Intent-to-treat population using last observation carried forward Least squares means adjusted for treatment, geographic region and baseline value p<0.01 compared to NESINA 25 mg or pioglitazone 30 mg In a 26-week, double-blind, placebo-controlled study, a total of 784 patients inadequately controlled on diet and exercise alone (mean baseline A1C = 8.4%) were randomized to one of seven treatment groups: placebo; metformin HCl 500 mg or metformin HCl 1000 mg twice daily; NESINA 12.5 mg twice daily; NESINA 25 mg daily; or NESINA 12.5 mg in combination with metformin HCl 500 mg or metformin HCl 1000 mg twice daily. Both coadministration treatment arms (NESINA 12.5 mg + metformin HCl 500 mg and NESINA 12.5 mg + metformin HCl 1000 mg) resulted in statistically significant improvements in A1C and FPG when compared with their respective individual alogliptin and metformin component regimens (Table 5). Coadministration treatment arms demonstrated improvements in two-hour postprandial glucose (PPG) compared to NESINA alone or metformin alone (Table 5). A total of 12.3% of patients receiving NESINA 12.5 mg + metformin HCl 500 mg, 2.6% of patients receiving NESINA 12.5 mg + metformin HCl 1000 mg, 17.3% of patients receiving NESINA 12.5 mg, 22.9% of patients receiving metformin HCl 500 mg, 10.8% of patients receiving metformin HCl 1000 mg and 38.7% of patients receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, race or baseline BMI. The mean decrease in body weight was similar between metformin alone and NESINA when coadministered with metformin. Table 5. Glycemic Parameters at Week 26 for NESINA and Metformin Alone and in Combination in Patients with Type 2 Diabetes Intent-to-treat population using last observation on study prior to discontinuation of double-blind study medication or sulfonylurea rescue therapy for patients needing rescue Least squares means adjusted for treatment, geographic region and baseline value p<0.05 when compared to metformin and NESINA alone Compared using logistic regression Intent-to-treat population using data available at Week 26 14.2 Combination Therapy Add-On Therapy to Metformin A total of 2081 patients with type 2 diabetes participated in two 26-week, double-blind, placebo-controlled studies to evaluate the efficacy and safety of NESINA as add-on therapy to metformin. In both studies, patients were inadequately controlled on metformin at a dose of at least 1500 mg per day or at the maximum tolerated dose. All patients entered a four-week, single-blind placebo run-in period prior to randomization. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment periods received glycemic rescue therapy. In the first 26-week, placebo-controlled study, a total of 527 patients already on metformin (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on a stable dose of metformin (median dose = 1700 mg) during the treatment period. NESINA 25 mg in combination with metformin resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 6). A total of 8% of patients receiving NESINA 25 mg and 24% of patients receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, baseline BMI or baseline metformin dose. The mean decrease in body weight was similar between NESINA and placebo when given in combination with metformin. Table 6. Glycemic Parameters at Week 26 in a Placebo-Controlled Study of NESINA as Add-On Therapy to Metformin* Intent-to-treat population using last observation on study Least squares means adjusted for treatment, baseline value, geographic region and baseline metformin dose p<0.001 compared to placebo In the second 26-week, double-blind, placebo-controlled study, a total of 1554 patients already on metformin (mean baseline A1C = 8.5%) were randomized to one of 12 double-blind treatment groups: placebo; 12.5 mg or 25 mg of NESINA alone; 15 mg, 30 mg or 45 mg of pioglitazone alone; or 12.5 mg or 25 mg of NESINA in combination with 15 mg, 30 mg or 45 mg of pioglitazone. Patients were maintained on a stable dose of metformin (median dose = 1700 mg) during the treatment period. Coadministration of NESINA and pioglitazone provided statistically significant improvements in A1C and FPG compared to placebo, to NESINA alone or to pioglitazone alone when added to background metformin therapy (Table 7, Figure 3). In addition, improvements from baseline A1C were comparable between NESINA alone and pioglitazone alone (15 mg, 30 mg and 45 mg) at Week 26. A total of 4%, 5% or 2% of patients receiving NESINA 25 mg with 15 mg, 30 mg or 45 mg pioglitazone, 33% of patients receiving placebo, 13% of patients receiving NESINA 25 mg and 10%, 15% or 9% of patients receiving pioglitazone 15 mg, 30 mg or 45 mg alone required glycemic rescue. Improvements in A1C were not affected by gender, age or baseline BMI. The mean increase in body weight was similar between pioglitazone alone and NESINA when coadministered with pioglitazone. Table 7. Glycemic Parameters in a 26-Week Study of NESINA, Pioglitazone and NESINA in Combination with Pioglitazone when Added to Metformin* Intent-to-treat population using last observation on study Least squares means adjusted for treatment, geographic region, metformin dose and baseline value p≤0.01 when compared to corresponding doses of pioglitazone and NESINA alone Figure 3. Change from Baseline in A1C at Week 26 with NESINA and Pioglitazone Alone and NESINA in Combination with Pioglitazone When Added to Metformin Add-On Therapy to a Thiazolidinedione In a 26-week, placebo-controlled study, a total of 493 patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea (10 mg) (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on a stable dose of pioglitazone (median dose = 30 mg) during the treatment period; those who were also previously treated on metformin (median dose = 2000 mg) or sulfonylurea (median dose = 10 mg) prior to randomization were maintained on the combination therapy during the treatment period. All patients entered into a four-week, single-blind placebo run-in period prior to randomization. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment period received glycemic rescue therapy. The addition of NESINA 25 mg once daily to pioglitazone therapy resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, compared to placebo (Table 8). A total of 9% of patients who were receiving NESINA 25 mg and 12% of patients receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, baseline BMI or baseline pioglitazone dose. Clinically meaningful reductions in A1C were observed with NESINA compared to placebo regardless of whether subjects were receiving concomitant metformin or sulfonylurea (-0.2% placebo versus -0.9% NESINA) therapy or pioglitazone alone (0% placebo versus -0.52% NESINA). The mean increase in body weight was similar between NESINA and placebo when given in combination with pioglitazone. Table 8. Glycemic Parameters in a 26-Week, Placebo-Controlled Study of NESINA as Add-On Therapy to Pioglitazone* Intent-to-treat population using last observation on study Least squares means adjusted for treatment, baseline value, geographic region, baseline treatment regimen (pioglitazone, pioglitazone + metformin or pioglitazone + sulfonylurea) and baseline pioglitazone dose p<0.01 compared to placebo Add-on Combination Therapy with Pioglitazone and Metformin In a 52-week, active-comparator study, a total of 803 patients inadequately controlled (mean baseline A1C = 8.2%) on a current regimen of pioglitazone 30 mg and metformin at least 1500 mg per day or at the maximum tolerated dose were randomized to either receive the addition of NESINA 25 mg or the titration of pioglitazone 30 mg to 45 mg following a four-week, single-blind placebo run-in period. Patients were maintained on a stable dose of metformin (median dose = 1700 mg). Patients who failed to meet prespecified hyperglycemic goals during the 52-week treatment period received glycemic rescue therapy. In combination with pioglitazone and metformin, NESINA 25 mg was shown to be statistically superior in lowering A1C and FPG compared with the titration of pioglitazone from 30 mg to 45 mg at Week 26 and at Week 52 (Table 9; results shown only for Week 52). A total of 11% of patients in the NESINA 25 mg treatment group and 22% of patients in the pioglitazone up-titration group required glycemic rescue. Improvements in A1C were not affected by gender, age, race or baseline BMI. The mean increase in body weight was similar in both treatment arms. Table 9. Glycemic Parameters in a 52-Week, Controlled Study of NESINA as Add-On Combination Therapy with Pioglitazone and Metformin* Intent-to-treat population using last observation on study Least squares means adjusted for treatment, baseline value, geographic region and baseline metformin dose. Noninferior and statistically superior to metformin + pioglitazone at the 0.025 one-sided significance level § p<0.001 compared to pioglitazone 45 mg + metformin Add-On Therapy to a Sulfonylurea In a 26-week, placebo-controlled study, a total of 500 patients inadequately controlled on a sulfonylurea (mean baseline A1C = 8.1%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on a stable dose of glyburide (median dose = 10 mg) during the treatment period. All patients entered into a four-week, single-blind, placebo run-in period prior to randomization. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment period received glycemic rescue therapy. The addition of NESINA 25 mg to glyburide therapy resulted in statistically significant improvements from baseline in A1C at Week 26 when compared to placebo (Table 10). Improvements in FPG observed with NESINA 25 mg were not statistically significant compared with placebo. A total of 16% of patients receiving NESINA 25 mg and 28% of those receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, baseline BMI or baseline glyburide dose. The mean change in body weight was similar between NESINA and placebo when given in combination with glyburide. Table 10. Glycemic Parameters in a 26-Week, Placebo-Controlled Study of NESINA as Add-On Therapy to Glyburide* Intent-to-treat population using last observation on study Least squares means adjusted for treatment, baseline value, geographic region and baseline glyburide dose p<0.01 compared to placebo Add-On Therapy to Insulin In a 26-week, placebo-controlled study, a total of 390 patients inadequately controlled on insulin alone (42%) or in combination with metformin (58%) (mean baseline A1C = 9.3%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on their insulin regimen (median dose = 55 IU) upon randomization and those previously treated with insulin in combination with metformin (median dose = 1700 mg) prior to randomization continued on the combination regimen during the treatment period. Patients entered the trial on short-, intermediate- or long-acting (basal) insulin or premixed insulin. Patients who failed to meet prespecified hyperglycemic goals during the 26-week treatment period received glycemic rescue therapy. The addition of NESINA 25 mg once daily to insulin therapy resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 11). A total of 20% of patients receiving NESINA 25 mg and 40% of those receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, baseline BMI or baseline insulin dose. Clinically meaningful reductions in A1C were observed with NESINA compared to placebo regardless of whether subjects were receiving concomitant metformin and insulin (-0.2% placebo versus -0.8% NESINA) therapy or insulin alone (0.1% placebo versus -0.7% NESINA). The mean increase in body weight was similar between NESINA and placebo when given in combination with insulin. Table 11. Glycemic Parameters in a 26-Week, Placebo-Controlled Study of NESINA as Add-On Therapy to Insulin* Intent-to-treat population using last observation on study Least squares means adjusted for treatment, baseline value, geographic region, baseline treatment regimen (insulin or insulin + metformin) and baseline daily insulin dose p<0.05 compared to placebo 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 Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a3768c7e-aa4c-44d3-bc53-43bb7346c0b0 美国FDA批准三个治疗2型糖尿病的新药物 2013年1月25日，美国食品药品监督管理局（FDA）批准了3种用于2型糖尿病成人患者改善血糖水平的新药： Nesina（alogliptin）片、Kazanoc（alogliptin和盐酸二甲双胍）片以及Oseni（alogliptin和吡格列酮）片，配合节食与运动使用。 Alogliptin是一种全新的活性成分，而二甲双胍和盐酸吡格列酮已获FDA批准用于2型糖尿病。美国2型糖尿病是最常见疾病，患者约有24万人，占确诊糖尿病患者的90％以上。 2型糖尿病是胰岛素抑制或不能产生足够胰岛素导致的高血糖。由于血糖水平较高，2型糖尿病患者发生严重并发症的风险，包括心脏病、失明、神经和肾脏损害。 Nesina、Kazano和Oseni可单独使用，也可与其他2型糖尿病药物包括磺脲类药物、胰岛素联合应用。但这些药品不能用于1型糖尿病或血、尿酮增加（糖尿病酮酸中毒）患者的治疗。 一项包括大约8500名2型糖尿病患者的14个临床试验，证明了Nesina的安全、有效性。 Nesina可降低衡量血糖控制指标的糖化血红蛋白（HbA1c）水平，服用26周后比安慰剂降低HbA1c值0.4％至0.6％。 FDA要求Nesina进行上市后研究，包括：心血管预后试验；强化药物警戒计划以监测肝脏异常、严重胰腺炎和严重过敏反应；根据儿童研究公平法案（PREA）进行三个儿童用药研究，包括一个剂量调查研究和两个安全性和有效性研究 –单用Nesina和Nesina与二甲双胍合用。 Nesina常见的不良反应包括：鼻塞或流涕、头痛和上呼吸道感染。涉及2500多例2型糖尿病患者的4个临床试验，证明了Kazano的安全性和有效性。 Kazano可进一步降低糖化血红蛋白水平，治疗26周后，降低糖化血红蛋白值超过Nesina 1.1％，超过二甲双胍0.5％。 FDA要求Kazano进行二个上市后研究：强化药物警戒计划以观察肝脏异常、严重胰腺炎和严重过敏反应和根据儿童研究公平法案（PREA）进行儿童安全性和有效性研究。 Kazano说明书带有黑框警告，与二甲双胍合用会导致血乳酸性酸中毒。 Kazano的常见不良反应包括:上呼吸道感染、鼻塞或流涕、咽痛、腹泻、头痛、高血压、腰痛和尿路感染。 一项涉及1500多名患者2型糖尿病患者的4个临床试验，证明了Oseni的安全性和有效性。 Oseni可进一步降低糖化血红蛋白，超过吡格列酮0.4％至0.6％，超过Alogliptin 0.4%至0.9％以上。 美国食品和药物管理局要求Oseni强化药物警戒计划以监测肝脏异常、严重胰腺炎和严重过敏反应。 Oseni说明书带有黑框警告，与吡格列酮合用会导致心脏衰竭。 Oseni最常见不良反应：鼻塞或流涕、喉咙痛、背部疼痛和上呼吸道感染。 Nesina、Kazano和Oseni由位于伊利诺伊州迪尔菲尔德的武田制药美国公司负责销售