Alogliptin Benzoate

Contraindications

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

Warnings/Precautions

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis reported during postmarketing experience.1 FDA has been evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous pancreatic cell changes in patients with type 2 diabetes mellitus receiving incretin mimetics.17 18 FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete, or when FDA has additional information to report.17

FDA has recommended that clinicians continue to follow the recommendations in the prescribing information for incretin mimetics.17 Manufacturer states that patients should be observed carefully for signs and symptoms of pancreatitis.1 If pancreatitis is suspected, promptly discontinue alogliptin and institute appropriate management.1

Not known if history of pancreatitis increases risk for pancreatitis with alogliptin.1

Severe Arthralgia

Severe, disabling joint pain reported 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 Symptoms resolved upon discontinuance of the DPP-4 inhibitor; symptoms recurred in some patients when the same or another DPP-4 inhibitor was restarted.1 41 Consider DPP-4 inhibitors as a possible cause of severe joint pain and discontinue if appropriate.1 41 (See Advice to Patients.)

Sensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, angioedema, severe adverse cutaneous reactions including Stevens-Johnson syndrome) reported.1

Promptly discontinue alogliptin if a serious hypersensitivity reaction is suspected, investigate other potential causes, and institute alternative antidiabetic therapy.1 (See Advice to Patients.)

Use with caution in patients with a history of angioedema to other DDP-4 inhibitors; unknown whether such patients will be predisposed to angioedema with alogliptin.1

Hepatic Effects

Fatal and nonfatal hepatic failure reported.1 Assess hepatic function prior to alogliptin initiation; use with caution in patients with abnormal liver function test results.1

Promptly assess liver function in patients with signs or symptoms indicating liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).1 Interrupt alogliptin treatment if clinically important liver enzyme elevations and if liver function test abnormalities persist or worsen.1 Do not restart the drug in these patients without another explanation for the test abnormalities.1

Concomitant Therapy with Hypoglycemic Agents

When used in combination with an insulin secretagogue (e.g., a sulfonylurea) or insulin, consider reducing the dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.1

Cardiovascular Effects

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

Possible increased risk of heart failure, particularly in patients with history of heart failure or renal impairment.42 In a randomized, placebo-controlled, double-blind study in which alogliptin 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

Consider potential risks and benefits of alogliptin therapy prior to use in patients at higher risk for heart failure.1 42 Monitor patients for manifestations of heart failure.1 42 (See Advice to Patients.) If heart failure develops, institute appropriate treatment and consider discontinuance of alogliptin.1 42

Use of Fixed Combinations

When used in fixed combination with metformin hydrochloride or pioglitazone, consider the cautions, precautions, and contraindications associated with metformin or pioglitazone.1

Specific Populations

Category B.1

Distributed into milk in rats; not known whether distributed into human milk.1 Use caution.1

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

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Moderate hepatic impairment decreased alogliptin total exposure.1 (See Absorption: Special Populations, under Pharmacokinetics.) Data lacking in severe hepatic impairment.1

Fixed combination of alogliptin and metformin hydrochloride not recommended in patients with hepatic impairment.2

Renal impairment increases AUC.1 (See Absorption: Special Populations, under Pharmacokinetics.) Dosage adjustment recommended for patients with moderate or severe renal impairment or end-stage renal disease.1 (See Renal Impairment under Dosage and Administration.)

Fixed combination of alogliptin and metformin hydrochloride contraindicated in patients with renal impairment.2

Assess renal function prior to initiation of therapy and periodically thereafter.1

Common Adverse Effects

Alogliptin monotherapy: Nasopharyngitis,1 headache,1 upper respiratory tract infection.1

Alogliptin/metformin hydrochloride fixed combination: Upper respiratory tract infection,2 nasopharyngitis,2 diarrhea,2 hypertension,2 headache,2 back pain,2 urinary tract infection.2

Alogliptin/pioglitazone fixed combination: Nasopharyngitis,3 back pain,3 upper respiratory tract infection.3

Mainly renally excreted; CYP-related metabolism is negligible.1

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP2C8, 2C9, and 3A4 inhibitors: No clinically important interactions observed with the inhibitors tested.1

CYP1A2, 2C8, 2C9, 2D6, and 3A4 substrates: No clinically important interactions observed with the substrates tested.1

Substrates or Inhibitors of P-glycoprotein Transport Systems

No clinically important interactions observed with the substrates or inhibitors tested.1

Specific Drugs

Storage

Oral

25°C (may be exposed to 15–30°C).1 2 3

Keep alogliptin/pioglitazone fixed-combination tablets in tightly closed container and protect from moisture and humidity.3

Keep alogliptin/metformin hydrochloride fixed-combination tablets in tightly closed container.2

• Inhibits DPP-4, an enzyme that inactivates incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).1 13

• 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

• Selectively inhibits DPP-4 with no effect on DPP-8 or DPP-9 in vitro at concentrations approximating those from therapeutic exposures.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.