Alogliptin

ALOGLIPTIN- alogliptin benzoate tablet, film coated
A-S Medication Solutions

1 INDICATIONS AND USAGE

1.1 Monotherapy and Combination Therapy

Alogliptin tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14)].

Important Limitations of Use

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

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

The recommended dose of alogliptin tablets is 25 mg once daily. Alogliptin tablets may be taken with or without food.

2.2 Patients with Renal Impairment

No dose adjustment of alogliptin tablets is necessary for patients with mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min).

The dose of alogliptin tablets is 12.5 mg once daily for patients with moderate renal impairment (CrCl ≥30 to <60 mL/min).

The dose of alogliptin tablets is 6.25 mg once daily for patients with severe renal impairment (CrCl ≥15 to <30 mL/min) or with end-stage renal disease (ESRD) (CrCl <15 mL/min or requiring hemodialysis). Alogliptin tablets may be administered without regard to the timing of dialysis. Alogliptin tablets have not been studied in patients undergoing peritoneal dialysis [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Because there is a need for dose adjustment based upon renal function, assessment of renal function is recommended prior to initiation of alogliptin tablets therapy and periodically thereafter.

3 DOSAGE FORMS AND STRENGTHS

• 25 mg tablets are light red, oval, biconvex, film-coated, with “TAK ALG-25” printed on one side.
• 12.5 mg tablets are yellow, oval, biconvex, film-coated, with “TAK ALG-12.5” printed on one side.
• 6.25 mg tablets are light pink, oval, biconvex, film-coated, with “TAK ALG-6.25” printed on one side.

4 CONTRAINDICATIONS

History of a serious hypersensitivity reaction to alogliptin-containing products, such as anaphylaxis, angioedema or severe cutaneous adverse reactions.

5 WARNINGS AND PRECAUTIONS

5.1 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 tablets 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 tablets 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 alogliptin tablets.

After initiation of alogliptin tablets, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, alogliptin tablets should promptly be discontinued and appropriate management should be initiated.

5.2 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 tablets and 89 (3.3%) of patients treated with placebo were hospitalized for congestive heart failure.

Consider the risks and benefits of alogliptin tablets 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 alogliptin tablets.

5.3 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin tablets. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue alogliptin tablets, assess for other potential causes for the event and institute alternative treatment for diabetes [see Adverse Reactions (6.2)]. 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 alogliptin tablets.

5.4 Hepatic Effects

There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking alogliptin tablets, although some of the reports contain insufficient information necessary to establish the probable cause [see Adverse Reactions (6.2)].

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 tablets 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 tablets 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, alogliptin tablets should be interrupted and investigation done to establish the probable cause. Alogliptin tablets should not be restarted in these patients without another explanation for the liver test abnormalities.

5.5 Use with Medications Known to Cause Hypoglycemia

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 alogliptin tablets.

5.6 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.

5.7 Bullous Pemphigoid

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

5.8 Macrovascular Outcomes

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

6 ADVERSE REACTIONS

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

• Pancreatitis [see Warnings and Precautions (5.1)]
• Heart Failure [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Hepatic Effects [see Warnings and Precautions (5.4)]
• Severe and Disabling Arthralgia [see Warnings and Precautions (5.6)]
• Bullous Pemphigoid [see Warnings and Precautions (5.7)]

6.1 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.

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 tablets, 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 tablets 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 tablets 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 tablets 25 mg compared to 8.4% with placebo or 6.2% with active comparator.

Adverse reactions reported in ≥4% of patients treated with alogliptin tablets 25 mg and more frequently than in patients who received placebo are summarized in Table 1.

Table 1. Adverse Reactions Reported in ≥4% Patients Treated with Alogliptin Tablets 25 mg and More Frequently Than in Patients Given Placebo in Pooled Studies

	Number of Patients (%)
	Alogliptin Tablets25 mg	Placebo	Active Comparator
	N=6447	N=3469	N=2257
Nasopharyngitis	309 (4.8)	152 (4.4)	113 (5.0)
Upper Respiratory Tract Infection	287 (4.5)	121 (3.5)	113 (5.0)
Headache	278 (4.3)	101 (2.9)	121 (5.4)

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 tablets compared to 1.6% with placebo. The use of alogliptin tablets as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy study comparing alogliptin tablets to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with alogliptin tablets compared to 26% with glipizide (Table 2).

Table 2. Incidence and Rate of Hypoglycemia * in Placebo and Active-Controlled Studies when Alogliptin Tablets Were Used as Add-On Therapy to Glyburide, Insulin, Metformin, Pioglitazone or Compared to Glipizide or Metformin

* Adverse reactions of hypoglycemia were based on all reports of symptomatic and asymptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population. † Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level or loss of consciousness or seizure.
Add-On to Glyburide(26 Weeks)	Alogliptin Tablets 25 mg	Placebo
	N=198	N=99
Overall (%)	19 (9.6)	11 (11.1)
Severe (%)†	0	1 (1)
Add-On to Insulin (± Metformin)(26 Weeks)	Alogliptin Tablets 25 mg	Placebo
	N=129	N=129
Overall (%)	35 (27)	31 (24)
Severe (%)†	1 (0.8)	2 (1.6)
Add-On to Metformin(26 Weeks)	Alogliptin Tablets 25 mg	Placebo
	N=207	N=104
Overall (%)	0	3 (2.9)
Severe (%)†	0	0
Add-On to Pioglitazone(± Metformin or Sulfonylurea)(26 Weeks)	Alogliptin Tablets 25 mg	Placebo
	N=199	N=97
Overall (%)	14 (7.0)	5 (5.2)
Severe (%)†	0	1 (1)
Compared to Glipizide(52 Weeks)	Alogliptin Tablets 25 mg	Glipizide
	N=222	N=219
Overall (%)	12 (5.4)	57 (26)
Severe (%)†	0	3 (1.4)
Compared to Metformin(26 Weeks)	Alogliptin Tablets 25 mg	Metformin 500 mgtwice daily
	N=112	N=109
Overall (%)	2 (1.8)	2 (1.8)
Severe (%)†	0	0
Add-On to Metformin Compared to Glipizide(52 Weeks)	Alogliptin Tablets 25 mg	Glipizide
	N=877	N=869
Overall (%)	12 (1.4)	207 (23.8)
Severe (%)†	0	4 (0.5)

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

Renal Impairment

In glycemic control trials in patients with type 2 diabetes, 3.4% of patients treated with alogliptin tablets and 1.3% of patients treated with placebo had renal function adverse reactions. The most commonly reported adverse reactions were renal impairment (0.5% for alogliptin tablets and 0.1% for active comparators or placebo), decreased creatinine clearance (1.6% for alogliptin tablets and 0.5% for active comparators or placebo) and increased blood creatinine (0.5% for alogliptin tablets and 0.3% for active comparators or placebo) [see Use in Specific Populations (8.6)].

In the EXAMINE trial of high CV risk type 2 diabetes patients, 23% of patients treated with alogliptin tablets and 21% of patients treated with placebo had an investigator reported renal impairment adverse reaction. The most commonly reported adverse reactions were renal impairment (7.7% for alogliptin tablets and 6.7% for placebo), decreased glomerular filtration rate (4.9% for alogliptin tablets and 4.3% for placebo) and decreased renal clearance (2.2% for alogliptin tablets and 1.8% for placebo). Laboratory measures of renal function were also assessed. Estimated glomerular filtration rate decreased by 25% or more in 21.1% of patients treated with alogliptin tablets and 18.7% of patients treated with placebo. Worsening of chronic kidney disease stage was seen in 16.8% of patients treated with alogliptin tablets and in 15.5% of patients treated with placebo.