Metformin and Pioglitazone

ACTOPLUS MET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use ACTOPLUS MET is not recommended to treat type 1 diabetes mellitus or diabetic ketoacidosis. ACTOPLUS MET is a combination of pioglitazone, a thiazolidinedione agonist of peroxisome proliferator receptor gamma, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: Not recommended for treatment of type 1 diabetes or diabetic ketoacidosis.

ACTOPLUS MET combines two antihyperglycemic agents: pioglitazone and metformin. Pioglitazone Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

Obtain liver tests before initiation. If abnormal, use caution when treating with ACTOPLUS MET, investigate the probable cause, treat (if possible), and follow appropriately. Take orally with meals to reduce gastrointestinal adverse reactions with metformin. Individualize the starting dose based on the patient’s current regimen and titrate the dosage gradually, as needed after assessing therapeutic response and tolerability. The maximum recommended total daily dosage is pioglitazone 45 mg and metformin 2,550 mg. Recommended starting dosage in patients with NYHA Class I or Class II congestive heart failure is 15 mg of pioglitazone and 850 mg of metformin HCl orally once daily. Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR).

ACTOPLUS MET is contraindicated in patients with: Established NYHA Class III or IV heart failure at the time of ACTOPLUS MET initiation. Severe renal impairment (eGFR below 30 mL/min). A history of serious hypersensitivity to pioglitazone, metformin HCl, or any of the excipients in ACTOPLUS MET. Acute or chronic metabolic acidosis, including diabetic ketoacidosis. In patients with established New York Heart Association (NYHA) Class III or IV heart failure at the time of ACTOPLUS MET initiation. In patients with severe renal impairment: (eGFR below 30 mL/min). In patients with a history of serious hypersensitivity to pioglitazone, metformin HCl, or any of the excipients in ACTOPLUS MET.

Boxed warning (congestive heart failure and lactic acidosis): Congestive Heart Failure Thiazolidinediones, including pioglitazone, which is a component of ACTOPLUS MET ®, cause or exacerbate congestive heart failure in some patients. After initiation of ACTOPLUS MET, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). 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. Edema: Dose-related edema may occur. Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination with ACTOPLUS MET.

The following serious adverse reactions are discussed elsewhere in the labeling: Congestive heart failure Lactic acidosis Edema Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Hepatic Effects Urinary Bladder Tumors Fractures Macular Edema Vitamin B 12 Deficiency Most common adverse reactions (>5%) are upper respiratory tract infection, edema, diarrhea, headache and weight gain.

Strong CYP2C8 inhibitors (e.g., gemfibrozil): Limit ACTOPLUS MET dose to 15 mg/850 mg daily. CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine), may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. Alcohol: Warn patients against excessive alcohol intake. Use of insulin secretagogues or insulin use may increase the risk for hypoglycemia and may require dose reduction. Topiramate may decrease pioglitazone concentrations.

Storage Store at 25°C (77°F), excursions permitted to 15°-30°C (59°-86°F). Keep container tightly closed, and protect from moisture and humidity.