Warnings and Precautions—for KAZANOLactic 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. Temporarily discontinue in patients undergoing radiologic studies with intravascular iodinated contrast materials or any surgical procedures necessitating restricted intake of food and fluids. Lactic acidosis due to metformin accumulation during therapy is fatal in approximately 50% of cases. The risk increases in patients with renal impairment, congestive heart failure requiring drug treatment, and with increasing age. Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually. Warnings and Precautions—for OSENI Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms. Edema: Dose-related edema may occur. Use with caution in patients with edema. Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. Bladder cancer: Data suggest an increased risk of bladder cancer in pioglitazone users. Data also suggest that the risk increases with duration of use. Do not use OSENI in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. Tell patients to promptly report any sign of hematuria or other symptoms such as dysuria or urinary urgency as these may be due to bladder cancer. Macular edema: Macular edema has been reported in some patients taking pioglitazone. Recommend regular eye exams. Instruct patients to report any visual changes promptly. Ovulation: Therapy with pioglitazone may result in ovulation in some premenopausal anovulatory women. Warnings and Precautions—for NESINA, KAZANO, and OSENI Acute pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue NESINA, KAZANO, or OSENI. Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin such as anaphylaxis, angioedema or severe cutaneous adverse reactions. In such cases, promptly discontinue NESINA, KAZANO, or OSENI, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. Use caution in a patient with a history of angioedema with another DPP-4i because it is unknown whether such patients will be predisposed to angioedema. Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. Baseline liver test panel is recommended. If liver injury is detected, promptly interrupt NESINA, KAZANO, or OSENI and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart NESINA, KAZANO, or OSENI if liver injury is confirmed and no alternate etiology can be found. Use with caution in patients with liver disease. Hypoglycemia: Insulin and insulin secretagogues are known to cause hypoglycemia. A lower dose of the insulin or insulin secretagogue may be required to minimize the risk when used in combination with NESINA, KAZANO, or OSENI. Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with NESINA, KAZANO, OSENI, or any other anti-diabetic drug. Adverse Reactions Most common adverse reactions (greater than or equal to 4% of patients treated with NESINA 25 mg and more frequently than in patients who received placebo) were nasopharyngitis (4.4%), headache (4.2%), and upper respiratory tract infection (4.2%).