AHFS Class:

• Dipeptidyl Peptidase-4 (DPP-4) Inhibitors 68:20.05

Generic Name(s):

• Alogliptin Benzoate

• Alogliptin and Metformin

• Alogliptin and Pioglitazone

Chemical Name:

• 2-[[6-[(3 R )-3-Amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2 H )-pyrimidinyl]methyl]-benzonitrile monobenzoate

Molecular Formula:

• C₁₈H₂₁N₅O₂•C₇H₆O₂

Alogliptin benzoate, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is an antidiabetic agent.1,13

Type 2 Diabetes Mellitus

Alogliptin benzoate is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1,4,12,15 Alogliptin is used as initial therapy in combination with metformin hydrochloride or pioglitazone as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with both alogliptin and metformin or pioglitazone is appropriate.1,2,3,5 Alogliptin also is used in combination with other oral antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptor_γ [PPAR_γ] agonist [thiazolidinedione]) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control.1,2,3,5,6,7,8,9,10,11,15

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).698,704,705 (See Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.) In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, sodium-glucose cotransporter 2 [SGLT2] inhibitor, DPP-4 inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698,704 Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another agent) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.698,704 In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic drug classes with complementary mechanisms of action.698

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.698,704 Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA_1c by approximately 0.7-1%.704 In addition, early initiation of combination therapy may help more rapidly attain glycemic goals and extend the time to treatment failure.704

Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.698,704,705,706 Some experts recommend DPP-4 inhibitors as one of several classes of drugs for use in combination therapy, particularly in patients with both postprandial and fasting plasma glucose elevations.21,698,704 When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.704 While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698,704 For additional information regarding the initiation of insulin therapy in patients with diabetes mellitus, see Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

The manufacturer states that alogliptin is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.1,2,3

Alogliptin Monotherapy

Efficacy of alogliptin as monotherapy for the management of type 2 diabetes mellitus has been established in a double-blind, placebo-controlled study of 26 weeks' duration in a total of 329 patients.1,4 Alogliptin (12.5 or 25 mg once daily) improved glycemic control as evidenced by a reduction in glycosylated hemoglobin (HbA_1c) as well as in fasting plasma glucose concentrations compared with placebo.1,4 HbA_1c was reduced by approximately 0.6% (from a mean baseline HbA_1c concentration of about 8%) in patients receiving alogliptin 25 mg, compared with no change in HbA_1c in those receiving placebo.1,4

In a double-blind, active-controlled study of 52 weeks' duration in 441 patients 65-87 years of age, alogliptin (25 mg once daily) was noninferior to glipizide (5-10 mg daily) in reducing HbA_1c.12 Mean reductions in HbA_1c from baseline (mean HbA_1c of 7.5%) were 0.14% with alogliptin and 0.09% with glipizide.12 Patients receiving alogliptin also experienced lower risk of hypoglycemia and lost weight (loss of 0.62 kg) compared with patients receiving glipizide, who experienced weight gain (0.6 kg).12

Combination Therapy

Efficacy of the combination of alogliptin and pioglitazone as initial therapy in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise is supported by results of a 26-week randomized, active-controlled study.1,3,5 Patients receiving initial therapy with alogliptin (25 mg daily) in combination with pioglitazone (30 mg daily) had greater improvements in HbA_1c and fasting plasma glucose than those receiving alogliptin monotherapy or pioglitazone monotherapy.1,3,5 Mean reductions in HbA_1c from baseline (mean HbA_1c of 8.8%) were 1% with alogliptin 25 mg once daily, 1.2% with pioglitazone 30 mg once daily, and 1.7% with alogliptin 25 mg once daily in combination with pioglitazone 30 mg once daily.1,3,5 The proportion of patients who achieved an HbA_1c of 7% or less was greater with alogliptin and pioglitazone combination therapy (63%) than with alogliptin (24%) or pioglitazone (34%) monotherapy.1,3,5

In another 26-week, randomized trial in patients who had inadequate glycemic control with diet and exercise, patients receiving initial therapy with the combination of alogliptin (12.5 mg twice daily) and metformin hydrochloride (500 mg or 1 g twice daily) had greater improvements in HbA_1c and fasting plasma glucose than those receiving placebo, metformin monotherapy, or alogliptin monotherapy.1,2 Mean reductions in HbA_1c from baseline (mean HbA_1c of 8.4%) were 0.6% with alogliptin 12.5 mg twice daily, 0.7% with metformin hydrochloride 500 mg twice daily, 1.1% with metformin hydrochloride 1 g twice daily, 1.2% with alogliptin 12.5 mg and metformin hydrochloride 500 mg twice daily, and 1.6% with alogliptin 12.5 mg and metformin hydrochloride 1 g twice daily, while HbA_1c increased by 0.1% with placebo.1,2 In this trial, 47% of patients receiving alogliptin 12.5 mg and metformin hydrochloride 500 mg twice daily and 59% of those receiving alogliptin 12.5 mg and metformin hydrochloride 1 g twice daily achieved a mean HbA_1c of less than 7%, compared with 20% of those receiving alogliptin 12.5 mg twice daily as monotherapy and 27 or 34% of those receiving metformin hydrochloride 500 mg or 1 g twice daily as monotherapy.1,2

Efficacy of alogliptin in combination with metformin, a sulfonylurea, or a thiazolidinedione in the management of type 2 diabetes mellitus (inadequately controlled with metformin monotherapy, metformin and a thiazolidinedione, or a sulfonylurea) has been established in several randomized, placebo- or active-controlled, double-blind studies.1,2,3,6,7,8,9,10 In these studies, addition of alogliptin (25 mg daily) to existing therapy improved glycemic control as evidenced by reductions in HbA_1c as well as in fasting plasma glucose concentrations, compared with placebo or existing therapy.1,2,3,5,6,7,8,9,10 In a 26-week study in patients receiving metformin hydrochloride (dosage of at least 1.5 g daily or maximum tolerated dosage), the addition of alogliptin resulted in a reduction of 0.6% in HbA_1c compared with a reduction of 0.1% in HbA_1c with placebo.1,2,6 In a 26-week study in patients receiving metformin hydrochloride (at least 1.5 g daily), the addition of alogliptin and pioglitazone (15, 30, or 45 mg daily) resulted in reductions of 1.3-1.6% in HbA_1c; addition of pioglitazone alone, alogliptin alone, or placebo resulted in HbA_1c reductions of 0.8-1, 0.9, or 0.1%, respectively.1,3,7

In a 26-week study in patients receiving a thiazolidinedione alone or in combination with metformin or a sulfonylurea, addition of alogliptin (25 mg once daily) or placebo resulted in reductions of 0.8 or 0.2%, respectively, in HbA_1c.1,3,8 Patients receiving metformin or a sulfonylurea at baseline continued these agents at the same dosage throughout the study.8

In a 52-week study in patients receiving metformin hydrochloride (at least 1.5 g daily or maximum tolerated dosage) and pioglitazone (30 mg daily), add-on therapy with alogliptin (25 mg daily) or increased dosage of pioglitazone (45 mg daily) resulted in a reduction of 0.7 or 0.3%, respectively, from a baseline HbA_1c of approximately 8.2%.1,2,3,9

In a 26-week study in patients receiving glyburide, addition of alogliptin (25 mg daily) resulted in a reduction of 0.5% in HbA_1c compared with addition of placebo.1,10

Efficacy of alogliptin in combination with insulin (with or without metformin) in the management of type 2 diabetes mellitus in patients who have inadequate glycemic control with insulin is supported by results of a 26-week, randomized, double-blind, placebo-controlled study.1,11 In this study, addition of alogliptin (25 mg once daily) to existing stable insulin (premixed insulin, or short-, intermediate- or long-acting [basal] insulin) therapy with or without metformin hydrochloride resulted in improvements in HbA_1c and fasting plasma glucose concentrations compared with the addition of placebo.1,11 Among patients also receiving metformin, addition of alogliptin reduced HbA_1c by 0.8% compared with 0.2% in those receiving add-on placebo; among patients receiving insulin monotherapy, addition of alogliptin reduced HbA_1c by 0.7% compared with 0.1% in those receiving add-on placebo.1

Administration

When administered as monotherapy, alogliptin may be administered orally once daily without regard to meals.1

When alogliptin is administered in fixed combination with metformin hydrochloride, the combination should be administered twice daily with food; dosage should be titrated gradually to minimize adverse GI effects of the metformin component.2 Fixed-combination tablets should be swallowed whole and should not be split before swallowing.2

When alogliptin is administered in fixed combination with pioglitazone, the combination should be administered once daily without regard to meals.3 Fixed-combination tablets should be swallowed whole and should not be split before swallowing.3

If a dose of alogliptin alone or in combination with metformin or pioglitazone is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule.1,2,3 If the missed dose is not remembered until the time of the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose.1,2,3

Dosage

Type 2 Diabetes Mellitus

Dosage of alogliptin benzoate is expressed in terms of alogliptin.1

Alogliptin Monotherapy

The recommended dosage of alogliptin for the management of type 2 diabetes mellitus is 25 mg once daily.1

Combination Therapy with Metformin Hydrochloride

Dosage of alogliptin in fixed combination with metformin hydrochloride should be individualized based on the patient's current antidiabetic regimen, effectiveness, and tolerability.2 Dosage should be increased gradually to reduce adverse GI effects of metformin.2

The maximum recommended dosage of alogliptin in fixed combination with metformin hydrochloride is 25 mg of alogliptin and 2 g of metformin hydrochloride daily.2

Combination Therapy with Pioglitazone

When the fixed-combination preparation containing alogliptin and pioglitazone is used in patients who have inadequate glycemic control with diet and exercise, the recommended initial dosage is 25 mg of alogliptin and 15 mg of pioglitazone once daily or 25 mg of alogliptin and 30 mg of pioglitazone once daily.3

When the fixed-combination preparation containing alogliptin and pioglitazone is used in patients who have inadequate glycemic control on alogliptin monotherapy, the recommended initial dosage is 25 mg of alogliptin and 15 mg of pioglitazone once daily or 25 mg of alogliptin and 30 mg of pioglitazone once daily.3

When the fixed-combination preparation containing alogliptin and pioglitazone is used in patients who have inadequate glycemic control on pioglitazone monotherapy, the recommended initial dosage is 25 mg of alogliptin and 15 mg of pioglitazone once daily, 25 mg of alogliptin and 30 mg of pioglitazone once daily, or 25 mg of alogliptin and 45 mg of pioglitazone once daily based on the patient's current antidiabetic therapy.3

When the fixed-combination preparation containing alogliptin and pioglitazone is used in patients who have inadequate glycemic control on metformin monotherapy, the recommended initial dosage is 25 mg of alogliptin and 15 mg of pioglitazone once daily or 25 mg of alogliptin and 30 mg of pioglitazone once daily.3

The maximum recommended daily dosage of alogliptin in fixed combination with pioglitazone is 25 mg of alogliptin and 45 mg of pioglitazone.3

Special Populations

No adjustment of alogliptin dosage is necessary in patients with mild renal impairment (creatinine clearance of 60 mL/minute or greater).1 In patients with moderate renal impairment (creatinine clearance of 30 to less than 60 mL/minute), the recommended dosage of alogliptin is 12.5 mg once daily.1 In patients with severe renal impairment (creatinine clearance of 15 to less than 30 mL/minute) or end-stage renal disease (creatinine clearance of 15 mL/minute or less or requiring hemodialysis), the recommended daily dosage is 6.25 mg once daily.1 Alogliptin may be administered without regard to the timing of hemodialysis.1

The fixed combination of alogliptin and metformin hydrochloride is contraindicated in patients with renal impairment.2 Assessment of renal function is recommended prior to initiation of alogliptin therapy and periodically thereafter.1

The fixed combination of alogliptin and pioglitazone is not recommended in patients with severe renal impairment or end-stage renal disease.3

No adjustment of alogliptin dosage is recommended in patients with mild to moderate hepatic impairment; data are lacking in patients with severe hepatic impairment.1

The fixed combination of alogliptin and metformin is not recommended in patients with hepatic impairment.2

No dosage adjustment is necessary based on age, gender, or race.1

The recommended initial dosage of the fixed combination of alogliptin and pioglitazone in patients with congestive heart failure (CHF) (New York Heart Association [NYHA] class I or II) is 25 mg of alogliptin and 15 mg of pioglitazone once daily.3

Contraindications

Known serious hypersensitivity (e.g., anaphylaxis, angioedema, severe adverse cutaneous reactions) to alogliptin.1

Warnings/Precautions

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis has been reported during postmarketing experience in patients receiving alogliptin.1 In clinical studies in patients with type 2 diabetes mellitus, acute pancreatitis was reported in 0.2% of patients receiving alogliptin 25 mg compared with less than 0.1% of patients receiving active comparators or placebo.1 In a randomized, double-blind study (EXAMINE) in 5380 patients with type 2 diabetes mellitus and recent acute coronary syndrome, acute pancreatitis was reported in 0.4 or 0.3% of patients receiving alogliptin or placebo, respectively.1,39 FDA has been evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous pancreatic cell changes (pancreatic duct metaplasia) in patients with type 2 diabetes mellitus receiving incretin mimetics (e.g., exenatide, liraglutide, sitagliptin, saxagliptin, alogliptin, linagliptin).17,18 These findings are based on examination of a small number of pancreatic tissue specimens taken from patients who died from unspecified causes while receiving an incretin mimetic.17 FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete, or when the agency has additional information to report.17

FDA has recommended that clinicians continue to follow the recommendations in the prescribing information for incretin mimetics.17 The manufacturer states that patients receiving alogliptin should be observed carefully for signs and symptoms of pancreatitis.1 If pancreatitis is suspected, alogliptin should be promptly discontinued and appropriate management instituted.1 It is not known whether patients with a history of pancreatitis are at increased risk for pancreatitis with alogliptin therapy.1

Severe Arthralgia

Severe, disabling joint pain has been reported during postmarketing experience in patients receiving DPP-4 inhibitors (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin).1,41 Onset of such symptoms has ranged from 1 day to years following initiation of therapy.1,41 Fever, chills, rash, and swelling accompanied joint pain in some patients, suggesting an immunologic reaction; some patients have required hospitalization.41 Symptoms resolved upon discontinuance of the DPP-4 inhibitor, usually in less than a month.1,41 In some patients, symptoms recurred when the same or another DPP-4 inhibitor was restarted.1,41 DPP-4 inhibitors should be considered as a possible cause of severe joint pain and should be discontinued if appropriate.1,41 (See Advice to Patients.)

Sensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, angioedema, severe adverse cutaneous reactions including Stevens-Johnson syndrome) have been reported in patients receiving alogliptin.1

If a serious hypersensitivity reaction is suspected, alogliptin should be promptly discontinued, other potential causes of the event should be investigated, and alternative antidiabetic therapy should be instituted.1 (See Advice to Patients.) Alogliptin should be used with caution in patients with a history of angioedema to other dipeptidyl peptidase-4 inhibitors because it is unknown whether such patients will be predisposed to angioedema with alogliptin.1

Hepatic Effects

Fatal and nonfatal hepatic failure have been reported during postmarketing experience in patients receiving alogliptin.1 In randomized controlled trials, serum alanine aminotransferase (ALT) elevations exceeding 3 times the upper limit of normal were observed in 1.3% of patients receiving alogliptin and 1.5% of all comparator-treated patients.1

Patients with type 2 diabetes mellitus may have fatty liver disease, which may cause liver function test abnormalities; such patients may also have other forms of liver function disease, many of which can be treated or managed.1 Therefore, hepatic function should be assessed prior to initiation of alogliptin, and the drug should be initiated with caution in patients with abnormal liver function test results.1

Liver function should be assessed promptly in patients who report signs or symptoms that may indicate liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).1 If the patient has clinically important liver enzyme elevations and if liver function test abnormalities persist or worsen, alogliptin therapy should be interrupted.1 Alogliptin should not be restarted in these patients without another explanation for the liver function test abnormalities.1

Concomitant Therapy with Hypoglycemic Agents

When alogliptin is used in combination with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the incidence of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy.1 Therefore, patients receiving alogliptin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.1

Heart Failure Risk

Alogliptin may increase the risk of heart failure, particularly in patients who have a history of heart failure or renal impairment.42 In a randomized, double-blind study (EXAMINE) in which alogliptin or placebo was added to standard care in 5380 patients with type 2 diabetes mellitus and recent acute coronary syndrome, 3.9% of patients receiving alogliptin experienced at least one hospitalization for heart failure compared with 3.3% of patients receiving placebo.1,39,40,42 The average duration of follow-up in this study was 1.5 years.42

The potential risks and benefits of alogliptin therapy should be considered prior to use in patients at higher risk for heart failure (e.g., history of heart failure or renal impairment).1,42 Patients receiving alogliptin-containing therapy should be monitored for manifestations of heart failure.1,42 (See Advice to Patients.) If heart failure develops, appropriate evaluation and management should be instituted according to current standards of care and consideration given to discontinuing alogliptin.1,42

Macrovascular Outcomes

The manufacturer states that evidence of macrovascular risk reduction with alogliptin or any other antidiabetic agent has not been conclusively demonstrated in clinical trials.1

Use of Fixed Combinations

When alogliptin is used in fixed combination with metformin hydrochloride or pioglitazone, the cautions, precautions, and contraindications associated with metformin hydrochloride or pioglitazone should be considered in addition to those associated with alogliptin.1

Specific Populations

Pregnancy

Category B.1 (See Users Guide.)

Lactation

Alogliptin is distributed into milk in lactating rats at a milk-to-plasma ratio of 2:1; it is not known whether the drug is distributed into human milk.1 Caution is advised if alogliptin is administered in nursing women.1

Pediatric Use

Safety and efficacy of alogliptin alone, in fixed combination with metformin, or in fixed combination with pioglitazone have not been established in pediatric patients1 younger than 18 years of age.1,2,3,24

Geriatric Use

Of 8507 patients in clinical trials of alogliptin, 24.3% were 65 years of age and older; 4% were 75 years of age and older.1 No substantial differences in safety and efficacy relative to younger adults were observed, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh class B), alogliptin total exposure was approximately 10% lower than values in healthy individuals.1 Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh class C).1 Caution should be exercised in patients with liver disease.1

Renal Impairment

In patients with mild renal impairment (creatinine clearance of 60 to less than 90 mL/minute), area under the plasma concentration-time curve (AUC) of alogliptin increased approximately 1.2-fold; the manufacturer does not recommend dosage adjustment of alogliptin in patients with mild renal impairment.1

However, dosage adjustment is recommended when the drug is used in patients with moderate or severe renal impairment or end-stage renal disease.1 (See Special Populations under Dosage and Administration: Dosage.) Plasma AUC of alogliptin was increased approximately twofold in patients with moderate renal impairment (creatinine clearance of 30 to less than 60 mL/minute), threefold in those with severe renal impairment (creatinine clearance of 15 to less than 30 mL/minute), and fourfold in those with end-stage renal disease (creatinine clearance of 15 mL/minute or less or requiring hemodialysis).1

Common Adverse Effects

Adverse effects reported in at least 4% of patients receiving alogliptin monotherapy and more commonly than with placebo include nasopharyngitis,1 headache,1 and upper respiratory tract infection.1

Adverse effects reported in at least 4% of patients receiving alogliptin in combination with metformin and more commonly than with placebo include upper respiratory tract infection,2 nasopharyngitis,2 diarrhea,2 hypertension,2 headache,2 back pain,2 and urinary tract infection.2

Adverse effects reported in at least 4% of patients receiving alogliptin in combination with pioglitazone and more commonly than with placebo include nasopharyngitis,3 back pain,3 and upper respiratory tract infection.3

Alogliptin is principally renally excreted; cytochrome P-450 (CYP)-related metabolism is negligible.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Alogliptin does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 and does not inhibit CYP1A2, 2C8, 2C9, 2C19, 3A4, or 2D6.1

Concurrent administration of alogliptin (100 mg once daily for 7 days) with a single dose of a CYP1A2 substrate (caffeine 200 mg), a CYP2C9 substrate (tolbutamide 500 mg), a CYP2D6 substrate (dextromethorphan 30 mg), or a CYP3A4 substrate (midazolam 4 mg) did not meaningfully increase the peak plasma concentrations or area under the concentration-time curve (AUC) of caffeine, tolbutamide, dextromethorphan, or midazolam.1 The manufacturer states that no dosage adjustment is necessary with such concomitant therapy.1

Drugs that are Substrates of P-glycoprotein Transport Systems

Concurrent administration of alogliptin (100 mg once daily for 7 days) with a single dose of a P-glycoprotein substrate (fexofenadine 80 mg) did not meaningfully increase the peak plasma concentration or AUC of fexofenadine.1 The manufacturer states that no dosage adjustment is necessary with such concomitant therapy.1

Atorvastatin

Concurrent administration of alogliptin (25 mg once daily for 7 days) and atorvastatin (80 mg once daily for 7 days) did not meaningfully alter the peak plasma concentrations or AUC of alogliptin or atorvastatin.1 The manufacturer states that no dosage adjustment is necessary.1

Cimetidine

Concurrent administration of alogliptin (100 mg once daily for 6 days) and cimetidine (400 mg once daily for 6 days) did not meaningfully alter the peak plasma concentrations or AUC of alogliptin or cimetidine.1 The manufacturer states that no dosage adjustment is necessary.1

Contraceptives, Hormonal

Concurrent administration of alogliptin (25 mg once daily for 21 days) and an estrogen-progestin contraceptive (ethinyl estradiol 35 mcg and norethindrone 1 mg once daily for 21 days) did not meaningfully alter the peak plasma concentrations or AUC of ethinyl estradiol or norethindrone; no dosage adjustment is necessary.1,13

Cyclosporine

Concurrent administration of a single dose of alogliptin (25 mg) and a single dose of cyclosporine (600 mg) did not meaningfully alter the peak plasma concentrations or AUC of alogliptin.1 The manufacturer states that no dosage adjustment is necessary.1

Digoxin

Concurrent administration of alogliptin (25 mg once daily for 10 days) and digoxin (0.2 mg once daily for 10 days) did not meaningfully alter the peak plasma concentrations or AUC of alogliptin or digoxin.1 The manufacturer states that no dosage adjustment is necessary.1

Fluconazole

Concurrent administration of a single dose of alogliptin (25 mg) and fluconazole (200 mg once daily for 7 days) did not meaningfully alter the peak plasma concentrations or AUC of alogliptin.1,13 The manufacturer states that no dosage adjustment is necessary.1

Gemfibrozil

Concurrent administration of a single dose of alogliptin (25 mg) and gemfibrozil (600 mg twice daily for 7 days) did not meaningfully alter the peak plasma concentrations or AUC of alogliptin.1,13 The manufacturer states that no dosage adjustment is necessary.1

Glyburide

Concurrent administration of alogliptin (25 mg once daily for 8 days) and a single dose of glyburide (5 mg) did not meaningfully alter the peak plasma concentrations or AUC of glyburide.1,14 No dosage adjustment is necessary.1,14

Ketoconazole

Concurrent administration of a single dose of alogliptin (25 mg) and ketoconazole (400 mg once daily for 7 days) did not meaningfully alter the peak plasma concentrations or AUC of alogliptin.1,13 The manufacturer states that no dosage adjustment is necessary.1

Metformin

Concurrent administration of alogliptin (100 mg once daily for 6 days) and metformin hydrochloride (1 g twice daily for 6 days) did not meaningfully alter the peak plasma concentrations or AUC of alogliptin or metformin.1 The manufacturer states that no dosage adjustment is necessary.1

Pioglitazone

Concurrent administration of alogliptin (25 mg once daily for 12 days) and pioglitazone (45 mg once daily for 12 days) did not meaningfully alter the peak plasma concentrations or AUC of alogliptin or pioglitazone.1,14 No dosage adjustment is necessary.1,14

Warfarin

Concurrent administration of alogliptin (25 mg once daily for 7 days) and warfarin sodium (stable dosage of 1-10 mg once daily for 7 days) did not alter the peak plasma concentrations or AUC of R - or S -warfarin; prothrombin time (PT) or international normalized ratio (INR) was not altered.1,13 The manufacturer states that no dosage adjustment is necessary.1

Description

Alogliptin inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).1,13 Alogliptin selectively inhibits DPP-4 with no effect on DPP-8 or DPP-9 in vitro at concentrations approximating those from therapeutic exposures.1 Alogliptin increases circulating concentrations of GLP-1 and GIP in a glucose-dependent manner.1

GLP-1 and GIP stimulate insulin secretion from pancreatic β-cells in a glucose-dependent manner (i.e., when glucose concentrations are elevated).1 GLP-1 also decreases glucagon secretion from pancreatic α-cells, leading to reduced hepatic glucose production.1

Alogliptin did not increase the QT interval corrected for rate (QT_c) at daily dosages of 50 or 400 mg daily for 7 days in a randomized, placebo-controlled, active-comparator (moxifloxacin) study; the 400-mg dose produced plasma concentrations 19-fold higher than the maximum recommended clinical dose of 25 mg.1

Following oral administration of a single dose of alogliptin (up to 800 mg) in healthy individuals, median time to peak plasma concentration was 1-2 hours;1,13,16 the drug has an absolute oral bioavailability of approximately 100%.1 Administration of alogliptin with food did not substantially alter total and peak exposure to the drug.1,13 Alogliptin does not undergo extensive metabolism; 60-80% of the dose is excreted unchanged.1,13,16 Following administration of a radiolabeled dose of alogliptin, approximately 89% of administered radioactivity was excreted in urine (76%) and feces (13%).1 Terminal elimination half-life of alogliptin is approximately 21 hours following a single dose of 25 mg.1,13

Advice to Patients

Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.1,24

Importance of informing patients of the potential risks and benefits of alogliptin.1,24 Importance of not using alogliptin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1,24

Importance of informing patient about the possibility of acute pancreatitis, which may be severe or fatal, with alogliptin therapy.1,24 Importance of patient informing clinicians about a history of pancreatitis, gallstones, alcoholism, or kidney or liver problems.1,24 Importance of informing patients about signs and symptoms of pancreatitis, including persistent severe abdominal pain sometimes radiating to the back that may or may not be accompanied by vomiting; importance of patient discontinuing alogliptin and promptly notifying clinician if such signs or symptoms are present.1,24

Importance of informing patients about possibility of heart failure with alogliptin therapy.1,24,42 Importance of clinicians asking patients about a history of heart failure or renal impairment prior to initiating alogliptin therapy.1,24,42 Importance of informing patients about signs and symptoms of heart failure (e.g., shortness of breath, weight gain, edema); importance of patients immediately contacting a clinician if manifestations of heart failure occur.1,42

Importance of informing patients of the possibility of severe and disabling joint pain with DPP-4 inhibitors (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin).1,24,41 Advise patients to contact a clinician promptly if severe and persistent joint pain occurs; patients should not discontinue the DPP-4 inhibitor without consulting their clinician.1,24,41

Importance of informing patient of risk of hypoglycemia, particularly if concomitant therapy with a sulfonylurea antidiabetic agent (i.e., insulin secretagogue) or insulin is used.1,24

Risk of serious allergic (hypersensitivity) reaction.1,24 If signs or symptoms of such reactions occur (e.g., rash, hives, swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing), importance of discontinuing alogliptin therapy and informing clinician promptly.1,24

Importance of informing patients about possibility of liver injury, sometimes fatal, with alogliptin.1,24 If signs or symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, unusual/unexplained fatigue, anorexia, dark urine, jaundice) occur, importance of discontinuing alogliptin therapy and informing clinician promptly.1,24

Importance of taking alogliptin exactly as directed by clinician.1,24 (See Dosage and Administration: Administration.)

Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1,24

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1,24

Importance of informing patients of other important precautionary information. 1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Takeda Pharmaceuticals America, Inc. Nesina^® (alogliptin) tablets prescribing information. Deerfield, IL; 2016 Apr.

2. Takeda Pharmaceuticals America, Inc. Kazano^® (alogliptin and metformin hydrochloride) tablets prescribing information. Deerfield, IL; 2015 Aug.

3. Takeda Pharmaceuticals America, Inc. Oseni^® (alogliptin and pioglitazone) tablets prescribing information. Deerfield, IL; 2015 Aug.

4. DeFronzo RA, Fleck PR, Wilson CA et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care . 2008; 31:2315-7. [PubMedCentral][PubMed 18809631]

5. Rosenstock J, Inzucchi SE, Seufert J et al. Initial combination therapy with alogliptin and pioglitazone in drug-naïve patients with type 2 diabetes. Diabetes Care . 2010; 33:2406-8. [PubMedCentral][PubMed 20724648]

6. Nauck MA, Ellis GC, Fleck PR et al. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract . 2009; 63:46-55. [PubMed 19125992]

7. DeFronzo RA, Burant CF, Fleck P et al. Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes. J Clin Endocrinol Metab . 2012; 97:1615-22. [PubMed 22419732]

8. Pratley RE, Reusch JE, Fleck PR et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Curr Med Res Opin . 2009; 25:2361-71. [PubMed 19650752]

9. Bosi E, Ellis GC, Wilson CA et al. Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study. Diabetes Obes Metab . 2011; 13:1088-96. [PubMed 21733058]

10. Pratley RE, Kipnes MS, Fleck PR et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes Metab . 2009; 11:167-76. [PubMed 19125778]

11. Rosenstock J, Rendell MS, Gross JL et al. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1c) without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab . 2009; 11:1145-52. [PubMed 19758359]

12. Rosenstock J, Wilson C, Fleck P. Alogliptin versus glipizide monotherapy in elderly type 2 diabetes mellitus patients with mild hyperglycaemia: a prospective, double-blind, randomized, 1-year study. Diabetes Obes Metab . 2013; :15:906-14.

13. Christopher R, Karim A. Clinical pharmacology of alogliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of Type 2 diabetes. Expert Rev Clin Pharmacol . 2009; 2:589-600. [PubMed 22112254]

14. Karim A, Laurent A, Munsaka M et al. Coadministration of pioglitazone or glyburide and alogliptin: pharmacokinetic drug interaction assessment in healthy participants. J Clin Pharmacol . 2009; 49:1210-9. [PubMed 19622714]

15. Berhan A, Berhan Y. Efficacy of alogliptin in type 2 diabetes treatment: a meta-analysis of randomized double-blind controlled studies. BMC Endocr Disord . 2013; 13:9. [PubMedCentral][PubMed 23452780]

16. Covington P, Christopher R, Davenport M et al. Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes. Clin Ther . 2008; 30:499-512. [PubMed 18405788]

17. Food and Drug Administration. Early communication: reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas. Silver Spring, MD; 2013 Mar 14. From FDA website. Accessed 31 July 2013. [Web]

18. Singh S, Chang HY, Richards TM et al. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med . 2013; 173:534-9. [PubMed 23440284]

19. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet . 2006; 368:1696-705. [PubMed 17098089]

20. Garber AJ, Abrahamson MJ, Barzilay JI et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract . 2013 Mar-Apr; 19:327-36.

21. Rodbard HW, Jellinger PS, Davidson JA et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract . 2009 Sep-Oct; 15:540-59.

22. Nathan DM, Buse JB, Davidson MB et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care . 2009; 32:193-203. [PubMedCentral][PubMed 18945920]

23. Bolen S, Feldman L, Vassy J et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med . 2007; 147:386-99. [PubMed 17638715]

24. Takeda Pharmaceuticals America, Inc. Nesina^® (alogliptin) tablets medication guide. Deerfield, IL; 2016 Apr.

39. White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med . 2013; 369:1327-35. [PubMed 23992602]

40. Zannad F, Cannon CP, Cushman WC et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet . 2015; 385:2067-76. [PubMed 25765696]

41. Food and Drug Administration. FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. Rockville, MD; 2015 Aug 28. From FDA website. [Web]

42. Food and Drug Administration. FDA Drug Safety Communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. Silver Spring, MD; 2016 April 5. From FDA website. [Web]

698. Garber AJ, Handelsman Y, Grunberger G et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm 2020 executive summary. Endocr Pract . 2020; 26:107-139. [PubMed 32022600]

704. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2020 . Diabetes Care . 2020; 43:S98-S110. [PubMed 31862752]

705. American Diabetes Association. 10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes-2020 . Diabetes Care . 2020; 43:S111-S134. [PubMed 31862753]

706. American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes-2020 . Diabetes Care . 2020; 43:S135-S151. [PubMed 31862754]