Usual Adult Dose for Diabetes Type 2

Individualize dose based on current regimen and concurrent medical condition:

For patients inadequately controlled on diet and exercise or metformin monotherapy:

• Initial dose: alogliptin-pioglitazone 25 mg/15 mg or 25 mg/30 mg orally once a day
• For patients on alogliptin requiring additional glycemic control:
• Initial dose: alogliptin-pioglitazone 25 mg/15 mg or 25 mg/30 mg orally once a day

For patients on pioglitazone requiring additional glycemic control:

• Initial dose: alogliptin-pioglitazone 25 mg/15 mg, 25 mg/30 mg, or 25 mg/45 mg orally once a day

For patients with congestive heart failure (NYHA Class I or II):

• Initial dose: alogliptin-pioglitazone 25 mg/15 mg orally once a day

For patients switching from individual components:

• Initial dose: Switch to combination product based on current therapy.

Titrate dose based on glycemic response as determined by hemoglobin A1c (HbA1c).
Maximum dose: Alogliptin 25 mg per day; Pioglitazone 45 mg per day.

Comments: When used in combination with insulin or insulin secretagogues such as sulfonylureas, a lower dose of insulin or the insulin secretagogue may be required to minimize the risk of hypoglycemia.

Use: As an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetess when treatment with both alogliptin and pioglitazone is appropriate.

Renal Dose Adjustments

Mild renal dysfunction (CrCl greater than or equal to 60 mL/min): No adjustment recommended.
Moderate renal dysfunction (CrCl 30 mL/min to less than 60 mL/min): alogliptin-pioglitazone 12.5 mg/15 mg, 12.5 mg/30 mg, or 12.5 mg/45 mg orally once a day
Severe renal dysfunction or ESRD: Not recommended.

For patients with severe renal impairment: coadministration of alogliptin 6.25 mg orally once a day with pioglitazone orally once a day may be considered, however, this dose is not available in a combination tablet.

Liver Dose Adjustments

Use caution:

• Obtain liver function test (LFT) panel prior to starting treatment; initiate treatment cautiously in patients with abnormal liver tests.
• If hepatoxicity is suspected, measure LFTs promptly; for significant liver enzyme elevations (greater than 3 x ULN) stop treatment and investigate cause.
• Do not restart treatment without an explanation for abnormal liver tests.

Dose Adjustments

For patients with congestive heart failure (NYHA Class I or II):

• Initial dose: alogliptin 25 mg-pioglitazone 15 mg orally once a day

Coadministration with Strong CYP450 2C8 Inhibitors:

• Maximum dose: alogliptin 25 mg-pioglitazone 15 mg orally once a day

Due to risk of hypoglycemia if used in combination with sulfonylurea, or insulin, a lower dose of the sulfonylurea or insulin should be considered.

Precautions

US BOXED WARNING: CONGESTIVE HEART FAILURE:

• Thiazolidinediones, including pioglitazone, can cause or exacerbate congestive heart failure in some patients
• After initiation of this drug and after each dose increase, monitor for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone must be considered.
• Not recommended in patients with symptomatic heart failure.
• Initiation in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for dosing related precautions

Dialysis

Data not available

Other Comments

Administration advice:

• Take orally once a day with or without food
• Tablets should not be split before swallowing
• If a dose is missed, patients should be advised not to double their next dose.

General:

• This combination drug is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis as it would not be effective in these settings.
• Adequate contraception should be discussed with all premenopausal women as pioglitazone use may result in ovulation in some premenopausal anovulatory women.
• The US FDA has released an updated review evaluating the risk of bladder cancer and it concludes that use of pioglitazone may be linked to an increased risk of bladder cancer; while a 10-year epidemiologic study did not find an increased risk, other studies have shown risk. Pioglitazone should not be used in patients with active bladder cancer and should be used very carefully in patients with a history of bladder cancer.

Monitoring:

• Cardiovascular: Monitor for unusually rapid increase in weight, edema, shortness of breath, or other symptoms of heart failure.
• Renal: Assess renal function baseline and periodically during therapy; monitor for the development of macroscopic hematuria, dysuria, or urinary urgency.
• Hepatic: Obtain a liver function test panel prior to starting therapy; monitor for signs and symptoms of hepatotoxicity.
• Monitor for signs and symptoms of pancreatitis.
• Monitor glycemic control.

Patient advice:

• Patients experiencing rapid weight gain, shortness of breath or other symptoms of heart failure should notify their health care professional promptly.
• Premenopausal anovulatory women may be at risk for pregnancy while on this drug; pregnancy risk should be discussed and adequate contraception offered.
• Instruct patients to promptly report signs and symptoms of pancreatitis, hepatotoxicity, and/or any new or increased bladder symptoms such as macroscopic hematuria, dysuria, or urinary urgency.
• Hypoglycemia may occur, more commonly when used in combination with insulin or a sulfonylurea.
• Patients should understand the importance of adhering to dietary instructions and regular physical activity; during periods of stress such as fever, trauma, infection, or surgery, management of diabetes may change and patients should be advised to seek medical advice.
• Instruct patients to contact their health care provider if they develop severe and persistent joint pain or develop blisters or erosions on skin.