OSENI® (alogliptin and pioglitazone) tablets

•Thiazolidinediones, including pioglitazone, cause or exacerbate congestive heart failure in some patients.

•After initiation of OSENI and after dose increases, monitor patients carefully 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 in OSENI must be considered.

•OSENI is not recommended in patients with symptomatic heart failure.

•Initiation of OSENI in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

OSENI tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: alogliptin and pioglitazone.

Alogliptin- Alogliptin is a selective, orally bioavailable inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (DPP-4).
Pioglitazone- Pioglitazone is an oral antihyperglycemic agent that acts primarily by decreasing insulin resistance.

Alogliptin
Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.

Pioglitazone
Pharmacologic studies indicate that pioglitazone improves insulin sensitivity in muscle and adipose tissue while inhibiting hepatic gluconeogenesis. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPAR?). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle and liver. Activation of PPAR? nuclear receptors modulates the transcription of a number of insulin-responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

Limitation of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis.

Do not initiate OSENI in patients with established NYHA Class III or IV heart failure.

WARNINGS AND PRECAUTIONS:

1. Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms.
2. Acute pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue OSENI.
3. Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin such as anaphylaxis, angioedema and severe cutaneous adverse reactions. In such cases, promptly discontinue OSENI, assess for other potential causes, institute appropriate monitoring and treatment and initiate alternative treatment for diabetes.
4. Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt OSENI and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart OSENI if liver injury is confirmed and no alternative etiology can be found. Use with caution in patients with liver disease.
5. Edema: Dose-related edema may occur.
6. Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health.
7. Bladder cancer: Preclinical and clinical trial data, and results from an observational study suggest an increased risk of bladder cancer in pioglitazone users. The observational data further suggest that the risk increases with duration of use. Do not use in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer.
8. Hypoglycemia: When an insulin secretagogue (e.g., sulfonylurea) or insulin is used in combination with OSENI, a lower dose of insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia.
9. Macular edema: Postmarketing reports. Recommend regular eye exams in all patients with diabetes according to current standards of care with prompt evaluation for acute visual changes.
10. Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with OSENI or any other antidiabetic drug.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. Limit the pioglitazone dose to 15 mg daily. (2.3, 7.1)

CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. (7.2)

USE IN SPECIFIC POPULATIONS
Nursing mothers: Discontinue drug or nursing, taking into consideration the importance of the drug to the mother.

See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide.

 Individualize the starting dose of OSENI based on the patient’s current regimen and concurrent medical condition but do not exceed a daily dose of alogliptin 25 mg and pioglitazone 45 mg.

Can be taken with or without food.

Limit initial dose of pioglitazone to 15 mg once daily in patients with NYHA Class I or II heart failure.

Adjust dose if moderate renal impairment.

OSENI is not recommended for patients with severe renal impairment or end-stage renal disease (ESRD) requiring dialysis.

The maximum recommended dose of pioglitazone is 15 mg once daily in patients taking strong CYP2C8 inhibitors (e.g., gemfibrozil).

Tablets:
25 mg alogliptin and 15 mg pioglitazone, 25 mg alogliptin and 30 mg pioglitazone, 25 mg alogliptin and 45 mg pioglitazone.

12.5 mg alogliptin and 15 mg pioglitazone, 12.5 mg alogliptin and 30 mg pioglitazone, 12.5 mg alogliptin and 45 mg pioglitazone.

Distributed by:
Takeda Pharmaceuticals America, Inc.
Deerfield, IL 60015
Revised: June 2013

OSENI, NESINA and ACTOS are trademarks of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and are used under license by Takeda Pharmaceuticals America, Inc.

©2013 Takeda Pharmaceuticals America, Inc.
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