KAZANO tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes mellitus: alogliptin and metformin HCl. Alogliptin Alogliptin is a selective, orally bioavailable inhibitor of the enzymatic activity of DPP-4. Chemically, alogliptin is prepared as a benzoate salt, which is identified as 2-({6-[(3 R )-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2 H )-yl}methyl)benzonitrile monobenzoate. It has a molecular formula of C 18 H 21 N 5 O 2 ∙C 7 H 6 O 2 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 HCl Metformin HCl ( N,N -dimethylimidodicarbonimidic diamide HCl) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin HCl is a white to off-white crystalline compound with a molecular formula of C 4 H 11 N 5 ∙HCl and a molecular weight of 165.63. Metformin HCl 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 HCl 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 HCl which is equivalent to 389.93 mg metformin base (12.5 mg/500 mg) or 1000 mg metformin HCl which is equivalent to 779.86 mg metformin base (12.5 mg/1000 mg). KAZANO tablets contain the following inactive ingredients: crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, and povidone; the tablets are film-coated with ferric oxide yellow, hypromellose 2910, talc, and titanium dioxide. Chemical Structure Chemical Structure

KAZANO is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. KAZANO is a combination of alogliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: Should not be used in patients with type 1 diabetes mellitus. Limitations of Use KAZANO is not recommended for use in patients with type 1 diabetes mellitus.

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 Tablets:12.5 mg alogliptin and 500 mg metformin HCl, 12.5 mg alogliptin and 1000 mg metformin HCl.

Individualize the starting dosage based on the patient's current regimen. Given orally twice daily with food. Adjust the dosage based on effectiveness and tolerability while not exceeding the maximum recommended daily dosage of 25 mg alogliptin and 2000 mg metformin HCl. Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). Do not use in patients with eGFR below 60 mL/min/1.73 m 2 . KAZANO may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures

Recommended Dosage Individualize the starting dosage of KAZANO based on the patient's current regimen. KAZANO should be taken orally twice daily with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin. Do not split tablets. Adjust the dosage based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin hydrochloride (HCl)

Recommendations for Use in Renal Impairment Assess renal function prior to initiation of KAZANO and periodically thereafter. KAZANO is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 . KAZANO is not recommended in patients with an eGFR between 30 and 59 mL/min/1.73 m 2 because these patients require a lower daily dosage of alogliptin than what is available in the fixed combination KAZANO product. Kazano requires no dose adjustment in patients with an eGFR of 60 mL/min/1.73 m 2 or greater

Discontinuation for Iodinated Contrast Imaging Procedures Discontinue KAZANO at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart KAZANO if renal function is stable .

Lactic acidosis: See boxed warning . Pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue KAZANO. Heart failure: Consider the risks and benefits of KAZANO prior to initiating treatment in patients at risk for heart failure. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of KAZANO. Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin such as anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If hypersensitivity reactions occur, discontinue KAZANO, treat promptly, and monitor until signs and symptoms resolve. 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. Vitamin B 12 deficiency: Metformin may lower vitamin B 12 levels. Measure hematologic parameters annually and B 12 at 2 to 3 year intervals and manage any abnormalties. Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating KAZANO. 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. Bullous pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue KAZANO. 5.1 Lactic Acidosis Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally greater than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of KAZANO. In KAZANO-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue KAZANO and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include : Before initiating KAZANO, obtain an eGFR. KAZANO is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 . KAZANO is not recommended in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 because these patients require a lower dosage of alogliptin than what is available in the fixed combination KAZANO product. Obtain an eGFR at least annually in all patients taking KAZANO. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. Drug Interactions The concomitant use of KAZANO with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation . Therefore, consider more frequent monitoring of patients. Age 65 or Greater The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients . Radiological Studies with Contrast Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop KAZANO at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart KAZANO if renal function is stable. Surgery and Other Procedures Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. KAZANO should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue KAZANO. Excessive Alcohol Intake Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving KAZANO. Hepatic Impairment Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of KAZANO in patients with clinical or laboratory evidence of hepatic disease

Pancreatitis Acute pancreatitis has been reported in the postmarketing setting and in randomized clinical trials. In glycemic control trials in patients with type 2 diabetes mellitus, acute pancreatitis was reported in 6 (0.2%) patients treated with alogliptin 25 mg and 2 (<0.1%) patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes mellitus and high cardiovascular (CV) risk), acute pancreatitis was reported in 10 (0.4%) patients treated with alogliptin and in 7 (0.3%) patients treated with placebo. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using KAZANO . After initiation of KAZANO, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, alogliptin should promptly be discontinued and appropriate management should be initiated

Heart Failure In the EXAMINE trial which enrolled patients with type 2 diabetes mellitus and recent acute coronary syndrome, 106 (3.9%) of patients treated with alogliptin and 89 (3.3%) of patients treated with placebo were hospitalized for congestive heart failure. Consider the risks and benefits of KAZANO prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Patients should be advised of the characteristic symptoms of heart failure and should be instructed to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of KAZANO

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 mellitus. Use caution in patients with a history of angioedema with another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with KAZANO

Hepatic Effects There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking alogliptin, although some of the reports contain insufficient information necessary to establish the probable cause . In glycemic control trials in patients with type 2 diabetes mellitus, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were reported in 1.3% of patients treated with alogliptin 25 mg and 1.7% of patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes mellitus and high cardiovascular (CV) risk), increases in serum alanine aminotransferase three times the upper limit of the reference range occurred in 2.4% of patients treated with alogliptin and in 1.8% of patients treated with placebo. 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

Vitamin B 12 Levels In metformin clinical trials of 29 week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on KAZANO and manage any abnormalities

Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dosage of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with KAZANO

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

Bullous Pemphigoid Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving KAZANO. If bullous pemphigoid is suspected, KAZANO should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

Carbionic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine), may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. Metformin HCl Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with KAZANO may increase the risk of lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide Drugs that Reduce Metformin Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis . Intervention: Consider the benefits and risks of concomitant use. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving KAZANO. Insulin Secretagogues and Insulin Clinical Impact: Coadministration of KAZANO with an insulin secretagogue (e.g., sulfonylurea) or with insulin may increase the risk of hypoglycemia. Intervention: Patients may require a lower dose of the insulin secretagogue or insulin. Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Intervention: 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. Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and isoniazid Alogliptin Cytochrome (CYP) P450, CYP-Substrates or Inhibitors Clinical Impact: Insulin Secretagogues and Insulin Insulin and insulin secretagogues are known to cause hypoglycemia. Coadministration of KAZANO with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia .