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.

2.1 Recommendations for All Patients

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Health care 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

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 (>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 >5 mcg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin HCl is very low (approximately 0.03 cases/1000 patient years, with approximately 0.015 fatal cases/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 adults 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 adults 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, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to recur. Later occurrence of gastrointestinal 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 non-fatal 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.

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

5.10  Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KAZANO or any other antidiabetic drug.

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.

6.2 Laboratory Abnormalities

6.3 Postmarketing Experience

Alogliptin

The following adverse reactions have been identified during the postmarketing use of alogliptin outside the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, and severe cutaneous adverse reactions including Stevens-Johnson syndrome; hepatic enzyme elevations; fulminant hepatic failure; and acute pancreatitis.

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 non-anion 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.

8.1 Pregnancy

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

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 3-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.

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:

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500 mg metformin hydrochloride (12.5 mg/500 mg) or

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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.

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

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 6 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).

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 2 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 2 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).

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.

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 4-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 pre-specified 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.

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.

17.1 Instructions

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Inform patients of the potential risks and benefits of KAZANO.

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The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in Warnings and Precautions (5.1), should be explained to patients. Patients should be advised to discontinue KAZANO immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgias, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of KAZANO, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

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Patients should be informed that acute pancreatitis has been reported during use of alogliptin. Patients should be informed that persistent, severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue KAZANO and contact their physician if persistent severe abdominal pain occurs.

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Patients should be informed that allergic reactions have been reported during use of alogliptin and metformin. If symptoms of allergic reactions (including skin rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients should be instructed to discontinue KAZANO and seek medical advice promptly.

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Patients should be informed that postmarketing reports of liver injury, sometimes fatal, have been reported during use of alogliptin. If signs or symptoms of liver injury occur, patients should be instructed to discontinue KAZANO and seek medical advice promptly.

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Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with KAZANO.

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Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving KAZANO.

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Inform patients that hypoglycemia can occur, particularly when an insulin secretagogue or insulin is used in combination with KAZANO. Explain the risks, symptoms, and appropriate management of hypoglycemia.

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Instruct patients to take KAZANO only as prescribed twice daily. KAZANO should be taken with food. If a dose is missed, advise patients not to double their next dose.

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Patients should be informed that the tablets must never be split.

Instruct patients to read the Medication Guide before starting KAZANO therapy and to reread each time the prescription is refilled. Instruct patients to inform their healthcare provider if an unusual symptom develops or if a symptom persists or worsens.

Distributed by:

Takeda Pharmaceuticals America, Inc.

Deerfield, IL  60015

Revised: April 2013

KAZANO is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and is used under license by Takeda Pharmaceuticals America, Inc.

© 2013 Takeda Pharmaceuticals America, Inc.

ALM143P R2