Alogliptin and pioglitazone

You should not use this medicine if you have severe or uncontrolled heart failure, active bladder cancer, or diabetic ketoacidosis (call your doctor for treatment with insulin). Alogliptin and pioglitazone is not for treating type 1 diabetes.

This medicine can cause or worsen congestive heart failure. Call your doctor at once if you have shortness of breath (even with mild exertion), swelling, or rapid weight gain.

Tell your doctor if you use insulin. Taking alogliptin and pioglitazone while you are using insulin may increase your risk of serious heart problems.

Other drugs may increase or decrease the effects of alogliptin and pioglitazone on lowering your blood sugar. Tell your doctor about all medications you use. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

• Antidiabetic Agent, Dipeptidyl Peptidase 4 (DPP-4) Inhibitor
• Antidiabetic Agent, Thiazolidinedione

Alogliptin inhibits dipeptidyl peptidase 4 (DPP-4) enzyme resulting in prolonged active incretin levels. Incretin hormones (eg, glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and decreasing glucagon secretion from pancreatic alpha cells. Decreased glucagon secretion results in decreased hepatic glucose production. Under normal physiologic circumstances, incretin hormones are released by the intestine throughout the day and levels are increased in response to a meal; incretin hormones are rapidly inactivated by the DPP-4 enzyme.

Pioglitazone is a thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion. It has a mechanism of action that is dependent on the presence of insulin for activity. Pioglitazone is a potent and selective agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). Activation of nuclear PPARgamma receptors influences the production of a number of gene products involved in glucose and lipid metabolism. PPARgamma is abundant in the cells within the renal collecting tubules; fluid retention results from stimulation by thiazolidinediones which increases sodium reabsorption.

Diabetes mellitus, type 2: Oral: Initial doses should be based on current dose of alogliptin and pioglitazone. Maximum: alogliptin 25 mg/pioglitazone 45 mg daily

Patients inadequately controlled on diet and exercise, metformin alone, or alogliptin alone: Initial dose: Alogliptin 25 mg/pioglitazone 15 mg or alogliptin 25 mg/pioglitazone 30 mg once daily

Patients inadequately controlled on pioglitazone alone: Initial dose: Alogliptin 25 mg per day plus current daily dose of pioglitazone given once daily

Patients with NYHA Class I or II heart failure: Initial dose: Alogliptin 25 mg/pioglitazone 15 mg once daily

Patients switching from individual alogliptin and pioglitazone administration: Initial doses should be based on current dose of alogliptin and pioglitazone given once daily

Concomitant use with insulin or insulin secretagogues: Reduced dose of insulin or insulin secretagogues (eg, sulfonylureas) may be needed.

Dosage adjustment with strong CYP2C8 inhibitors (eg, gemfibrozil): Maximum recommended dose: alogliptin 25 mg/pioglitazone 15 mg once daily

Concerns related to adverse effects:

• Arthralgia: Severe and disabling arthralgia has been reported with DPP-4 inhibitor use; onset may occur within one day to years after treatment initiation and may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-4 inhibitor therapy resumed. Discontinue use if severe joint pain results from DPP-4 inhibitor therapy.

• Bladder cancer: Clinical trial data is inconsistent regarding the risk of bladder cancer in patients exposed to pioglitazone. Given the uncertainty of the findings, the manufacturer recommends to avoid use in patients with active bladder cancer and consider risks versus benefits prior to initiating therapy in patients with a history of bladder cancer.

• Bullous pemphigoid: DPP-4 inhibitor use has been associated with development of bullous pemphigoid; cases have typically resolved with topical or systemic immunosuppressive therapy and discontinuation of DPP-4 inhibitor therapy. Advise patients to report development of blisters or erosions. Discontinue therapy if bullous pemphigoid is suspected and consider referral to a dermatologist.

• Edema: Dose-related edema, including new-onset or exacerbation of existing edema, has been reported with pioglitazone; use with caution in patients with edema or at risk for heart failure. Monitor for signs/symptoms of heart failure.

• Fractures: An increased incidence of bone fractures in females treated with pioglitazone has been observed; majority of fractures occurred in the lower limb and distal upper limb. Consider risk of fracture prior to initiation and during use.

• Heart failure/cardiac effects: [US Boxed Warning]: Thiazolidinediones, including pioglitazone, may cause or exacerbate heart failure; closely monitor for signs and symptoms of heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases; if heart failure develops, treat accordingly and consider dose reduction or discontinuation of alogliptin and pioglitazone. Monitor patients for signs and symptoms of heart failure (eg, dyspnea, edema, excessive/rapid weight gain). Not recommended for use in any patient with symptomatic heart failure. Initiation of therapy is contraindicated in patients with NYHA class III or IV heart failure; if used in patients with NYHA class I or II (systolic) heart failure, initiate at lowest dosage and monitor closely. Alogliptin may be associated with increased risk of hospitalization due to heart failure. Use with caution in patients with a history of heart failure; consider discontinuation of therapy if heart failure develops.

• Hematologic effects: Pioglitazone may decrease hemoglobin/hematocrit; effects may be related to increased plasma volume.

• Hepatotoxicity: Cases of fatal and nonfatal hepatic failure have been reported in postmarketing surveillance. Baseline liver function tests (serum transaminases) are recommended to rule out underlying liver diseases. Use with caution in patients with abnormal serum transaminases. Monitor and promptly evaluate serum transaminase levels in patients with symptoms of hepatic injury (eg, fatigue, anorexia, jaundice, dark urine, and/or abdominal pain). In patients with clinically significant transaminase elevations and/or persistent or worsening elevations, therapy should be interrupted. Therapy should only be resumed with caution in patients where an alternative cause of transaminase elevations has been determined.

• Hypersensitivity reactions: Rare hypersensitivity reactions, including anaphylaxis, angioedema, and/or severe dermatologic reactions such as Stevens-Johnson syndrome, have been reported in postmarketing surveillance; discontinue if signs/symptoms of hypersensitivity reactions occur. Use with caution if patient has experienced angioedema with other DPP-4 inhibitor use.

• Pancreatitis: Cases of acute pancreatitis have been reported with use. Monitor for signs/symptoms of pancreatitis; discontinue use immediately if pancreatitis is suspected and initiate appropriate management. Use with caution in patients with a history of pancreatitis as it is not known if this population is at greater risk.

• Weight gain: Dose-related weight gain observed with use; mechanism unknown but likely associated with fluid retention and fat accumulation.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with liver disease.

• Macular edema: Has been reported with thiazolidinedione use, including pioglitazone; some patients with macular edema presented with blurred vision or decreased visual acuity, and most had peripheral edema at time of diagnosis. Patients should be seen by an ophthalmologist if any visual symptoms arise during therapy and all diabetic patients should have regular eye exams.

• Renal impairment: Use with caution in patients with moderate renal dysfunction; dosing adjustment required. Not recommended in patients with severe renal dysfunction or end-stage renal disease (ESRD); appropriately adjusted dosage of individual components may be considered.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus (insulin-dependent, IDDM).

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

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.

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.

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

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.