Kazano

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

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). Keep container tightly closed.

Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015. Revised: Dec 2016

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 when treatment with both alogliptin and metformin is appropriate.

Important Limitations Of Use

KAZANO is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

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

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 m².

KAZANO is not recommended in patients with an eGFR between 30 and 60 mL/min/1.73 m² because these patients require a lower daily dosage of alogliptin than what is available in the fixed combination KAZANO product.

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 m²; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after the imaging procedure; restart KAZANO if renal function is stable.

KAZANO is contraindicated in patients with:

• Severe renal impairment (eGFR below 30 mL/min/1.73 m²).
• 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.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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. Metforminassociated 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 hydrochloride 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.

• Before initiating KAZANO, obtain an eGFR.
• KAZANO is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m².
• KAZANO is not recommended in patients with an eGFR between 30 and 60 mL/min/1.73 m² 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 (e.g. cationic drugs). 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 m²; 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, 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 and high cardiovascular (CV) risk), acute pancreatitis was reported in 10 (0.4%) of patients treated with alogliptin and in 7 (0.3%) of 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 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. 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, 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 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 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.

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 minimize 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.

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.

Macrovascular Outcomes

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

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

• Inform patients of the potential risks and benefits of KAZANO.
• 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.
• 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.
• Patients should be informed of the signs and symptoms of heart failure. Before initiating KAZANO, patients should be asked about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Patients should be instructed to contact their healthcare providers as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight, or swelling of the feet.
• 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.
• 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.
• Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with KAZANO.
• Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving KAZANO.
• 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.
• Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs.
• 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.
• 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.

Nonclinical Toxicology

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 area under the plasma concentration curve (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.

Use In Specific Populations

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 mg/kg 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.

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.

Pediatric Use

Safety and effectiveness of KAZANO in pediatric patients have not been established.

Geriatric Use

Alogliptin and Metformin Hydrochloride

Elderly patients are more likely to have decreased renal function. Monitor renal function in the elderly more frequently.

 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=9052) in clinical safety and efficacy studies treated with alogliptin, 2257 (24.9%) patients were 65 years and older and 386 (4.3%) 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.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal and cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients.

Renal Impairment

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. KAZANO is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m².

Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. KAZANO is not recommended in patients with hepatic impairment.

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 (e.g. cationic drugs). 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 m²; 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.

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 mg/kg 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.

The following serious adverse reactions are described below or elsewhere in the prescribing information:

• Pancreatitis
• Heart Failure
• Hypersensitivity Reactions
• Hepatic Effects
• Severe and Disabling Arthralgia
• Bullous Pemphigoid

Clinical Trials 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 reactions 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

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

A total of 14,778 patients with type 2 diabetes participated in 14 randomized, double-blind, controlled clinical trials of whom 9052 subjects were treated with alogliptin, 3469 subjects were treated with placebo and 2257 were treated with an active comparator. The mean duration of diabetes was seven years, the mean body mass index (BMI) was 31 kg/m² (49% of patients had a BMI ≥30 kg/m²), and the mean age was 58 years (26% of patients ≥65 years of age). The mean exposure to alogliptin was 49 weeks with 3348 subjects treated for more than one year.

In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse reactions was 73% in patients treated with alogliptin 25 mg compared to 75% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse reactions was 6.8% with alogliptin 25 mg compared to 8.4% 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

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.

In the EXAMINE trial, the incidence of investigator reported hypoglycemia was 6.7% in patients receiving alogliptin and 6.5% in patients receiving placebo. Serious adverse reactions of hypoglycemia were reported in 0.8% of patients treated with alogliptin and in 0.6% of patients treated with placebo.

Metformin Hydrochloride

Table 3. Most Common Adverse Reactions (≥5%) in a Placebo-Controlled Clinical Study of Metformin Monotherapy*

Laboratory Abnormalities

Alogliptin And Metformin Hydrochloride

No clinically meaningful differences were observed among treatment groups regarding hematology, serum chemistry or urinalysis results.

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.

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use. 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.

Alogliptin

Acute pancreatitis, hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, hepatic enzyme elevations, fulminant hepatic failure, severe and disabling arthralgia and bullous pemphigoid, diarrhea, constipation, nausea, and ileus.

Metformin

Cholestatic, hepatocellular, and mixed hepatocellular liver injury.

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 maximum recommended clinical dose of 25 mg, respectively). No serious adverse reactions 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. 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

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.

Absorption And Bioavailability

Alogliptin and Metformin Hydrochloride

In bioequivalence studies of KAZANO, the area under the plasma concentration 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 results in no significant 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 infusion 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, Ndemethylated, 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 occurs 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.