英文药名：Kazano(Alogliptin and Metformin HCl Tablets) 中文药名：阿格列汀/盐酸二甲双胍复方片剂 生产厂家：武田制药北美公司 药品介绍 2013年1月25日，美国食品与药物管理局(FDA)批准了选择性二肽基肽酶-4(DPP-4)抑制剂阿格列汀(alogliptin)的3种制剂上市，用于改善成人2型糖尿病的血糖水平。这3种制剂分别为阿格列汀片、阿格列汀与盐酸二甲双胍固定剂量复合片剂和阿格列汀与吡格列酮复合片剂(商品名依次为Nesina、Kazano和Oseni)。FDA发布的公告显示，这3种药物不适用于1型糖尿病或糖尿病酮症酸中毒患者。 14项纳入8500例2型糖尿病患者的临床试验证明了Nesina安全性和有效性。结果显示，治疗26周后，Nesina组比安慰剂组患者的糖化血红蛋白(HbA1c)水平低0.4%—0.6%。FDA正要求制造商进行5项关于Nesina的上市后研究，这5项研究分别是关于Nesina的心血管转归、加强肝功能异常监测、严重胰腺炎病例报告和严重超敏反应的研究，以及3项儿科研究(包括适宜剂量研究和2项关于安全性和有效性的研究)。Nesina最常见的不良反应包括鼻塞或流鼻涕，头痛和上呼吸道感染。 4项纳入2500例2型糖尿病患者的临床试验证明了Kazano的安全性和有效性。结果显示，患者治疗26周后，Kazano组的HbA1c水平比Nesina组降低了1.1%，比二甲双胍组降低了0.5%。FDA正要求制造商进行2项关于Kazano的上市后研究：关于加强肝功能异常监测、严重胰腺炎和严重超敏反应的研究和儿科用药的安全性和有效性研究。Kazano有一项加框警告为乳酸酸中毒，与应用二甲双胍有关。Kazano最常见不良反应为上呼吸道感染，鼻塞或鼻流涕和咽喉痛，腹泻，头痛，血压升高，后背痛以及泌尿道感染。 4项纳入1500余例2型糖尿病患者的临床试验证明了Oseni的安全性和有效性。结果显示，Oseni 组比吡格列酮单药治疗组的HbA1c水平额外降低0.4%—0.6%，比阿格列汀单药治疗组额外降低0.4%—0.9%。FDA要求加强Oseni应用者肝功能异常监测、严重胰腺炎和严重超敏反应的警戒性。Oseni的加框警告为心衰，与吡格列酮应用有关。Oseni最常见不良反应为鼻塞或鼻流涕和咽喉痛，后背痛以及上呼吸道感染。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use KAZANO safely and effectively. See full prescribing information for KAZANO. KAZANO (alogliptin and metformin HCl) tablets for oral administration Initial U.S. Approval: 2013 WARNING: LACTIC ACIDOSISSee full prescribing information for complete boxed warning • Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment and acute congestive heart failure. (5.1) • Symptoms include malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate. (5.1) • If acidosis is suspected, discontinue KAZANO and hospitalize the patient immediately. (5.1) RECENT MAJOR CHANGES Warnings and Precautions (5.10)   8/2015 INDICATIONS AND USAGE KAZANO is a dipeptidyl-peptidase-4 (DPP-4) inhibitor and a biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1.1) Important Limitation of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1.2) DOSAGE AND ADMINISTRATION • Individualize the starting dose of KAZANO based on the patient's current regimen. ( 2.1) • KAZANO should be taken twice daily with food. ( 2.1) • May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin HCl. ( 2.1) DOSAGE FORMS AND STRENGTHS Tablets: 12.5 mg alogliptin and 500 mg metformin HCl, 12.5 mg alogliptin and 1000 mg metformin HCl. (3) CONTRAINDICATIONS • Renal impairment. ( 4, 5.5) • Metabolic acidosis, including diabetic ketoacidosis. ( 4, 5.1) • History of a serious hypersensitivity reaction to alogliptin or metformin, components of KAZANO, such as anaphylaxis, angioedema or severe cutaneous adverse reactions. ( 4) WARNINGS AND PRECAUTIONS • Lactic acidosis: Warn against excessive alcohol intake. KAZANO is not recommended in hepatic impairment and is contraindicated in renal impairment. Ensure normal renal function before initiating and at least annually thereafter. ( 5.1) • Acute pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue KAZANO. ( 5.2) • Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin such as anaphylaxis, angioedema and severe cutaneous adverse reactions. In such cases, promptly discontinue KAZANO, 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 KAZANO and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart KAZANO if liver injury is confirmed and no alternative etiology can be found. ( 5.4) • Temporarily discontinue in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials or any surgical procedures necessitating restricted intake of food and fluids. ( 5.5) • Vitamin B 12 deficiency: Metformin may lower vitamin B 12 levels. Monitor hematologic parameters annually. ( 5.8) • Hypoglycemia: When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia. ( 5.9) • 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. ( 5.10) • Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KAZANO or any other antidiabetic drug. ( 5.11) ADVERSE REACTIONS Common adverse reactions reported in ≥4% of patients treated with coadministration of alogliptin with metformin were: upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension, headache, back pain and urinary tract infection. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-TAKEDA-7 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Cationic drugs eliminated by renal tubular secretion: Use with caution. (7.2) USE IN SPECIFIC POPULATIONS • Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. ( 8.1) • Pediatrics: Safety and effectiveness of KAZANO in patients below the age of 18 have not been established. ( 8.4) • Geriatric Use: Caution should be used when prescribing KAZANO to elderly patients because reduced renal functions are associated with increasing age. ( 8.5) 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 KAZANO is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings when treatment with both alogliptin and metformin is appropriate [see Clinical Studies (14)]. 1.2 Limitation of Use KAZANO 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 Recommendations for All Patients • Healthcare providers should individualize the starting dose of KAZANO based on the patient's current regimen. • KAZANO should be taken twice daily with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin. KAZANO tablets must not be split before swallowing. • Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin HCl. • The following doses are available: 12.5 mg alogliptin and 500 mg metformin HCl 12.5 mg alogliptin and 1000 mg metformin HCl 3 DOSAGE FORMS AND STRENGTHS • 12.5 mg/500 mg tablets are pale yellow, oblong, film-coated tablets with "12.5/500" debossed on one side and "322M" debossed on the other side • 12.5 mg/1000 mg tablets are pale yellow, oblong, film-coated tablets with "12.5/1000" debossed on one side and "322M" debossed on the other side 4 CONTRAINDICATIONS KAZANO is contraindicated in patients with: • Renal impairment (e.g., serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction and septicemia [see Warnings and Precautions (5.5)]. • Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin. • History of a serious hypersensitivity reaction to alogliptin or metformin, components of KAZANO, such as anaphylaxis, angioedema or severe cutaneous adverse reactions. 5 WARNINGS AND PRECAUTIONS 5.1 Lactic Acidosis Lactic acidosis is a rare but serious metabolic complication that can occur due to metformin accumulation during treatment with KAZANO and is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (more than 5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels of more than 5 mcg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin HCl is very low (approximately 0.03 cases per 1000 patient-years, with approximately 0.015 fatal cases per 1000 patient-years). In more than 20,000 patient-years’ exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, because alcohol potentiates the effects of metformin on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may frequently cause dose-dependent metabolic acidosis (in controlled trials, 32% and 67% for adjunctive treatment in adult and pediatric patients, respectively, and 15% to 25% for monotherapy of epilepsy, with decrease in serum bicarbonate to less than 20 mEq/L; 3% and 11% for adjunctive treatment in adult and pediatric patients, respectively, and 1% to 7% for monotherapy of epilepsy, with decrease in serum bicarbonate to less than 17 mEq/L) and may exacerbate the risk of metformin-induced lactic acidosis [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. The onset of lactic acidosis often is subtle and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. Patients should be educated to promptly report these symptoms should they occur. If present, KAZANO should be withdrawn until lactic acidosis is ruled out. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels and blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, GI symptoms, which are common during initiation of therapy, are unlikely to recur. Later occurrence of GI symptoms could be due to lactic acidosis or other serious disease. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms such as poorly controlled diabetes or obesity, vigorous physical activity or technical problems in sample handling. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery [see Contraindications (4)]. 5.2 Pancreatitis There have been postmarketing reports of acute pancreatitis in patients taking alogliptin. After initiation of KAZANO, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, alogliptin 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 KAZANO. 5.3 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue KAZANO, assess for other potential causes for the event and institute alternative treatment for diabetes [see Adverse Reactions (6.3)]. Use caution in patients with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with KAZANO. 5.4 Hepatic Effects There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking alogliptin, although the reports contain insufficient information necessary to establish the probable cause [see Adverse Reactions (6.3)]. 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 KAZANO therapy is recommended. Because impaired hepatic function has been associated with some cases of lactic acidosis with use of metformin, KAZANO should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. 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, KAZANO should be interrupted and investigation done to establish the probable cause. KAZANO should not be restarted in these patients without another explanation for the liver test abnormalities. 5.5 Monitoring of Renal Function Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment. Therefore, KAZANO is contraindicated in patients with renal impairment. Before initiation of KAZANO therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and KAZANO discontinued if evidence of renal impairment is present. Metformin treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. Use of Concomitant Medications that May Affect Renal Function or Metformin Disposition Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see Drug Interactions (7.2)], should be used with caution. Radiological Studies and Surgical Procedures Radiological studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography and computed tomography) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, KAZANO should be temporarily discontinued at the time of or prior to the procedure and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal. KAZANO therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal. 5.6 Hypoxic States Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on KAZANO therapy, the drug should be promptly discontinued. 5.7 Alcohol Intake Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake while receiving KAZANO. 5.8 Vitamin B12 Levels In controlled, 29-week clinical trials of immediate-release metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on KAZANO, and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at two- to three-year intervals may be useful. 5.9 Use with Medications Known to Cause Hypoglycemia Alogliptin 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 reduce the risk of hypoglycemia when used in combination with KAZANO. Metformin Hydrochloride Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking β-adrenergic blocking drugs. 5.10 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 a 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. 5.11 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KAZANO 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 practice. Alogliptin and Metformin Hydrochloride Over 2700 patients with type 2 diabetes have received alogliptin coadministered with metformin in four large, randomized, double-blind controlled clinical trials. The mean exposure to KAZANO was 58 weeks, with more than 1400 subjects treated for more than one year. These included two 26-week placebo-controlled studies, one 52-week active control study and an interim analysis of a 104-week active-controlled study. In the KAZANO arm, the mean duration of diabetes was approximately six years, the mean body mass index (BMI) was 31 kg/m2 (56% of patients had a BMI ≥30 kg/m2) and the mean age was 55 years (18% of patients ≥65 years of age). In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions was 74% in patients treated with KAZANO compared to 75% treated with placebo. Overall discontinuation of therapy due to adverse events was 6.2% with KAZANO compared to 1.9% in placebo, 6.4% in metformin and 5.0% in alogliptin. Adverse reactions reported in ≥4% of patients treated with KAZANO and more frequently than in patients who received alogliptin, metformin or placebo are summarized in Table 1. Table 1. Adverse Reactions Reported in ≥4% of Patients Treated with KAZANO and More Frequently than in Patients Receiving Either Alogliptin, Metformin or Placebo KAZANO − includes data pooled for patients receiving alogliptin 25 and 12.5 mg combined with various dose of metformin Alogliptin − includes data pooled for patients receiving alogliptin 25 and 12.5 mg ‡Metformin − includes data pooled for patients receiving various doses of metformin Hypoglycemia In a 26-week, double-blind, placebo-controlled study of alogliptin in combination with metformin, the number of patients reporting hypoglycemia was 1.9% in the alogliptin 12.5 mg with metformin HCl 500 mg, 5.3% in the alogliptin 12.5 mg with metformin HCl 1000 mg, 1.8% in the metformin HCl 500 mg and 6.3% in the metformin HCl 1000 mg treatment groups. In a 26-week placebo-controlled study of alogliptin 25 mg administered once daily as add-on to metformin regimen, the number of patients reporting hypoglycemic events was 0% in the alogliptin with metformin and 2.9% in the placebo treatment groups. In a 52-week, active-controlled, double-blind study of alogliptin once daily as add-on therapy to the combination of pioglitazone 30 mg and metformin compared to the titration of pioglitazone 30 mg to 45 mg and metformin, the number of patients reporting hypoglycemia was 4.5% in the alogliptin 25 mg with pioglitazone 30 mg and metformin group versus 1.5% in the pioglitazone 45 mg with metformin group. In an interim analysis conducted in a 104-week, double-blind, active-controlled study of alogliptin 25 mg in combination with metformin, the number of patients reporting hypoglycemia was 1.4% in the alogliptin 25 mg with metformin group versus 23.8% in the glipizide with metformin group. Alogliptin Approximately 8500 patients with type 2 diabetes have been treated with alogliptin 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 alogliptin 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 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 alogliptin 12.5 mg daily, alogliptin 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 alogliptin 25 mg compared to 62% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse events was 4.7% with alogliptin 25 mg compared to 4.5% with placebo or 6.2% with active comparator. Adverse reactions reported in ≥4% of patients treated with alogliptin 25 mg and more frequently than in patients who received placebo are summarized in Table 2. Table 2. Adverse Reactions Reported in ≥4% Patients Treated with Alogliptin 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 alogliptin 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 alogliptin 25 mg compared to 0.8% with all comparators. A single event of serum sickness was reported in a patient treated with alogliptin 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 alogliptin compared to 1.6% with placebo. The use of alogliptin as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy study comparing alogliptin to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with alogliptin compared to 26% with glipizide. Metformin Hydrochloride Table 3. Most Common Adverse Reactions (≥5%) in a Placebo-Controlled Clinical Study of Metformin Monotherapy Reactions that were more common in metformin than placebo-treated patients 6.2 Laboratory Abnormalities Alogliptin and Metformin Hydrochloride No clinically meaningful differences were observed among treatment groups regarding hematology, serum chemistry or urinalysis results. Alogliptin No clinically meaningful changes in hematology, serum chemistry or urinalysis were observed in patients treated with alogliptin. Metformin Hydrochloride Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on KAZANO, and any apparent abnormalities should be appropriately investigated and managed [see Warnings and Precautions (5.8)]. 6.3 Postmarketing Experience Alogliptin The following adverse reactions have been identified during the postmarketing use of alogliptin. 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 include 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 (5.2, 5.3, 5.4, 5.10). 7 DRUG INTERACTIONS Alogliptin Alogliptin is primarily renally excreted and CYP-related metabolism is negligible. No drug-drug interactions were observed with the CYP-substrates or inhibitors tested or with renally excreted drugs [see Clinical Pharmacology (12.3)]. Metformin Hydrochloride 7.1 Carbonic Anhydrase Inhibitors Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce nonanion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase. 7.2 Cationic Drugs Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of KAZANO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. 7.3 The Use of Metformin with Other Drugs Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and isoniazid. When such drugs are administered to a patient receiving KAZANO, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving KAZANO, the patient should be observed closely for hypoglycemia. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B Alogliptin and Metformin Hydrochloride There are no adequate and well-controlled studies in pregnant women with KAZANO or its individual components. Based on animal data, KAZANO is not predicted to increase the risk of developmental abnormalities. Because animal reproduction studies are not always predictive of human risk and exposure, KAZANO, like other antidiabetic medications, should be used during pregnancy only if clearly needed. No treatment-related fetal abnormalities occurred following concomitant administration of 100 mg/kg alogliptin with 150 mg/kg metformin to pregnant rats, or approximately 28 and two times the clinical dose of alogliptin (25 mg) and metformin (2000 mg), respectively (based on AUC). Alogliptin Alogliptin administered to pregnant rabbits and rats during the period of organogenesis was not teratogenic at doses of up to 200 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. Metformin Hydrochloride Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg, which represents an exposure of about two and six times the MRHD dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Metformin HCl should not be used during pregnancy unless clearly needed. 8.3 Nursing Mothers No studies have been conducted with the combined components of KAZANO. In studies performed with the individual components, both alogliptin and metformin are secreted in the milk of lactating rats. It is not known whether alogliptin and/or metformin are secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when KAZANO is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of KAZANO in pediatric patients have not been established. 8.5 Geriatric Use Alogliptin and Metformin Hydrochloride Elderly patients are more likely to have decreased renal function. Because metformin is contraindicated in patients with renal impairment, carefully monitor renal function in the elderly and use KAZANO with caution as age increases [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)]. Of the total number of patients (N = 2095) in clinical safety and efficacy studies, 343 (16.4%) patients were 65 years and older and 37 (1.8%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. While this and other reported clinical experiences have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be excluded. Alogliptin Of the total number of patients (N=8507) in clinical safety and efficacy studies treated with alogliptin, 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. Metformin Hydrochloride Controlled studies of metformin did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin should only be used in patients with normal renal function. The initial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population [see Contraindications (4), Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Alogliptin The highest doses of alogliptin 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 recommended clinical dose, respectively). No dose-limiting 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 alogliptin is dialyzable by peritoneal dialysis. Metformin Hydrochloride Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. 11 DESCRIPTION KAZANO tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: alogliptin and metformin hydrochloride. Alogliptin Alogliptin 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. Metformin Hydrochloride Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown: KAZANO is available as a tablet for oral administration containing 17 mg alogliptin benzoate equivalent to 12.5 mg alogliptin and: • 500 mg metformin hydrochloride (12.5 mg/500 mg) or • 1000 mg metformin hydrochloride (12.5 mg/1000 mg). KAZANO tablets contain the following inactive ingredients: mannitol, microcrystalline cellulose, povidone, crospovidone, and magnesium stearate; the tablets are film-coated with hypromellose 2910, talc, titanium dioxide and ferric oxide yellow. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Alogliptin and Metformin Hydrochloride KAZANO combines two antihyperglycemic agents with complementary and distinct mechanisms of action to improve glycemic control in patients with type 2 diabetes: alogliptin, a selective inhibitor of DPP-4, and metformin HCl, a member of the biguanide class. Alogliptin 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. Metformin Hydrochloride Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in special circumstances [see Warnings and Precautions (5.9)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease. 12.2 Pharmacodynamics Alogliptin Single-dose administration of alogliptin 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 alogliptin (at doses of 25 to 200 mg) than placebo. In a 16-week, double-blind, placebo-controlled study, alogliptin 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, alogliptin 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 alogliptin, inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing. 12.3 Pharmacokinetics Absorption and Bioavailability Alogliptin and Metformin Hydrochloride In bioequivalence studies of KAZANO, the area under the curve (AUC) and maximum concentration (Cmax) of both the alogliptin and the metformin component following a single dose of the combination tablet were bioequivalent to the alogliptin 12.5 mg concomitantly administered with metformin HCl 500 or 1000 mg tablets under fasted conditions in healthy subjects. Administration of KAZANO with food resulted in no change in total exposure (AUC) of alogliptin and metformin. Mean peak plasma concentrations of alogliptin and metformin were decreased by 13% and 28%, respectively, when administered with food. There was no change in time to peak plasma concentrations (Tmax) for alogliptin under fed conditions, however, there was a delayed Tmax for metformin of 1.5 hours. These changes are not likely to be clinically significant. Alogliptin The absolute bioavailability of alogliptin is approximately 100%. Administration of alogliptin with a high-fat meal resulted in no change in total and peak exposure to alogliptin. Alogliptin may therefore be administered with or without food. Metformin Hydrochloride The absolute bioavailability of metformin following administration of a 500 mg metformin HCl tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin HCl tablets 500 mg to 1500 mg and 850 mg to 2550 mg indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin HCl with food compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown. Distribution Alogliptin Following a single, 12.5 mg intravenous dose 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. Metformin Hydrochloride The apparent volume of distribution (V/F) of metformin following single oral doses of immediate release metformin HCl tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally less than 1 mcg/mL. During controlled clinical trials, which served as the basis for approval for metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses. Metabolism Alogliptin 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 (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. Metformin Hydrochloride Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Excretion and Elimination Alogliptin The primary route of elimination of [14C] alogliptin-derived radioactivity occurred 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. Metformin Hydrochloride Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Special Populations Renal Impairment Alogliptin and Metformin Hydrochloride Use of KAZANO in patients with renal impairment increases the risk for lactic acidosis. Because KAZANO contains metformin, KAZANO is contraindicated in patients with renal impairment [see Contraindications (4) and Warnings and Precautions (5.5)]. Hepatic Impairment KAZANO is not recommended in patients with hepatic impairment. KAZANO contains metformin and use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis [see Warnings and Precautions (5.4)]. Alogliptin 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. Metformin Hydrochloride No pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment. Gender Alogliptin No dose adjustment is necessary based on gender. Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Metformin Hydrochloride Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females. Geriatric KAZANO contains metformin, which is contraindicated in patients with renal impairment [see Warnings and Precautions (5.5)]. Due to declining renal function in the elderly, measurement of creatinine clearance should be obtained prior to initiation of therapy. Do not use KAZANO if renal function is not within normal range. Alogliptin No dose adjustment is necessary based on age. Age did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Metformin Hydrochloride Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. Pediatrics Studies characterizing the pharmacokinetics of alogliptin in pediatric patients have not been performed. Race Alogliptin No dose adjustment of alogliptin is necessary based on race. Race (white, black and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Metformin Hydrochloride No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51) and Hispanics (n=24). Drug Interactions Alogliptin and Metformin Hydrochloride Administration of alogliptin 100 mg once daily with metformin HCl 1000 mg twice daily for six days had no meaningful effect on the pharmacokinetics of alogliptin or metformin. Specific pharmacokinetic drug interaction studies with KAZANO have not been performed, although such studies have been conducted with the individual components of KAZANO (alogliptin and metformin). Alogliptin 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 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 alogliptin is administered concomitantly with the drugs described below (Figure 2). Figure 2. Effect of Other Drugs on the Pharmacokinetic Exposure of Alogliptin Metformin Hydrochloride Pharmacokinetic drug interaction studies have been performed on metformin (Tables 4 and 5). Table 4. Effect of Coadministered Drug on Plasma Metformin Systemic Exposure All metformin and coadministered drugs were given as single doses AUC = AUC 0-∞ Metformin hydrochloride extended-release tablets 500 mg Ratio of arithmetic means At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h Table 5. Effect of Metformin on Coadministered Drug Systemic Exposure All metformin and coadministered drugs were given as single doses AUC = AUC 0-∞ AUC 0-24 hr reported Ratio of arithmetic means, p-value of difference <0.05 Ratio of arithmetic means 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Alogliptin and Metformin Hydrochloride No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with KAZANO. The following data are based on findings in studies performed with alogliptin or metformin individually. Alogliptin 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). Metformin Hydrochloride Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg and 1500 mg/kg, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg. There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells) or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons. 14 CLINICAL STUDIES The coadministration of alogliptin and metformin has been studied in patients with type 2 diabetes inadequately controlled on either diet and exercise alone, on metformin alone or metformin in combination with a thiazolidinedione. There have been no clinical efficacy studies conducted with KAZANO; however, bioequivalence of KAZANO with coadministered alogliptin and metformin tablets was demonstrated, and efficacy of the combination of alogliptin and metformin has been demonstrated in three Phase 3 efficacy studies. A total of 2095 patients with type 2 diabetes were randomized in three double-blind, placebo- or active-controlled clinical safety and efficacy studies conducted to evaluate the effects of KAZANO on glycemic control. The racial distribution of patients exposed to study medication was 69.2% white, 16.3% Asian, 6.5% black and 8.0% other racial groups. The ethnic distribution was 24.3% Hispanic. Patients had an overall mean age of approximately 54.4 years (range 22 to 80 years). In patients with type 2 diabetes, treatment with KAZANO produced clinically meaningful and statistically significant improvements in A1C versus comparator. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with KAZANO appears to be related to the degree of A1C elevation at baseline. Alogliptin and Metformin Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise 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, alogliptin 12.5 mg twice daily, or alogliptin 25 mg daily; alogliptin 12.5 mg in combination with metformin HCl 500 mg or metformin HCl 1000 mg twice daily. Both coadministration treatment arms (alogliptin 12.5 mg + metformin HCl 500 mg and alogliptin 12.5 mg + metformin HCl 1000 mg) resulted in significant improvements in A1C (Figure 3) and FPG when compared with their respective individual alogliptin and metformin component regimens (Table 6). Coadministration treatment arms demonstrated improvements in two-hour postprandial glucose (PPG) compared to alogliptin alone or metformin alone (Table 6). A total of 12% of patients receiving alogliptin 12.5 mg + metformin HCl 500 mg, 3% of patients receiving alogliptin 12.5 mg + metformin HCl 1000 mg, 17% of patients receiving alogliptin 12.5 mg, 23% of patients receiving metformin HCl 500 mg, 11% of patients receiving metformin HCl 1000 mg and 39% 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 alogliptin when coadministered with metformin. Lipid effects were neutral. Table 6. Glycemic Parameters at Week 26 for Alogliptin 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 alogliptin alone Compared using logistic regression Intent-to-treat population using data available at Week 26 Figure 3. Change from Baseline A1C at Week 26 with Alogliptin and Metformin Alone and Alogliptin in Combination with Metformin Alogliptin and Metformin Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone In a 26-week, double-blind, placebo-controlled study, a total of 527 patients already on metformin (mean baseline A1C = 8%) were randomized to receive alogliptin 12.5 mg, alogliptin 25 mg, or placebo once daily. Patients were maintained on a stable dose of metformin HCl (median daily dose = 1700 mg) during the treatment period. Alogliptin 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 7). A total of 8% of patients receiving alogliptin 25 mg and 24% of patients receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, race, baseline BMI or baseline metformin dose. The mean decrease in body weight was similar between alogliptin 25 mg and placebo when given in combination with metformin. Lipid effects were also neutral. Table 7. Glycemic Parameters at Week 26 in a Placebo-Controlled Study of Alogliptin 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. Alogliptin Add-On Therapy in Patients with Type 2 Diabetes Inadequately Controlled on the Combination of Metformin and Pioglitazone 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 were randomized to either receive the addition of once-daily alogliptin 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 HCl (median daily 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, alogliptin 25 mg was shown to be statistically superior in lowering A1C and FPG compared with the titration of pioglitazone from 30 to 45 mg at Week 26 and at Week 52 (Table 8). A total of 11% of patients in the alogliptin 25 mg in combination with pioglitazone 30 mg and metformin treatment group and 22% of patients in the up titration of pioglitazone in combination with metformin treatment 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. Lipid effects were neutral. Table 8. Glycemic Parameters at Week 52 in an Active-Controlled Study of Alogliptin as Add-On Combination Therapy to Metformin and Pioglitazone* Intent-to-treat population using last observation on study Least squares means adjusted for treatment, baseline value, geographic region, and baseline metformin dose Non-inferior and statistically superior to metformin plus pioglitazone at the 0.025 one-sided significance level p<0.001 compared to pioglitazone 45 mg + metformin 16 HOW SUPPLIED/STORAGE AND HANDLING KAZANO tablets are available in the following strengths and packages: 12.5 mg/500 mg tablet: pale yellow, oblong, film-coated tablets with "12.5/500" debossed on one side and "322M" debossed on the other side, available in: NDC 64764-335-60 Bottles of 60 tablets NDC 64764-335-80 Bottles of 180 tablets NDC 64764-335-77 Bottles of 500 tablets 12.5 mg/1000 mg tablet: pale yellow, oblong, film-coated tablets with "12.5/1000" debossed on one side and "322M" debossed on the other side, available in: NDC 64764-337-60 Bottles of 60 tablets NDC 64764-337-80 Bottles of 180 tablets NDC 64764-337-77 Bottles of 500 tablets Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=83cb7914-a683-47bb-a713-f2bc6a596bd2 http://www.druginformation.com/RxDrugs/A/Alogliptin%20and%20Metformin%20HCl%20Tablets.html