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。
这3种药物均由武田制药公司制造。
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 ACIDOSIS
See full prescribing information for complete boxed warning
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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)
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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)
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If acidosis is suspected, discontinue KAZANO and hospitalize the patient immediately. (5.1)
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
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Individualize the starting dose of KAZANO based on the patient's current regimen. (2.1)
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KAZANO should be taken twice daily with food. (2.1)
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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
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Renal impairment. (4, 5.5)
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Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1)
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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
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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)
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Acute pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue KAZANO. (5.2)
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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)
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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)
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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)
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Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually. (5.8)
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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)
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Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KAZANO or any other antidiabetic drug. (5.10)
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
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Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. (8.1)
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Pediatrics: Safety and effectiveness of KAZANO in patients below the age of 18 have not been established. (8.4)
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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 FDA-approved patient labeling.
Revised: 08/2013
Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
WARNING: LACTIC ACIDOSIS
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Lactic acidosis is a rare but serious complication that 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 [see Warnings and Precautions (5.1)].
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The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate [see Warnings and Precautions (5.1)].
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If acidosis is suspected, KAZANO (alogliptin and metformin HCl) should be discontinued and the patient hospitalized immediately [see Warnings and Precautions (5.1)].
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
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Healthcare providers should individualize the starting dose of KAZANO based on the patient's current regimen.
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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.
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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.
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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
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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
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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
