Trade Names:ActoPlus Met- Tablets pioglitazone 15 mg/metformin 500 mg- Tablets pioglitazone 15 mg/metformin 850 mg
Pioglitazone, a thiazolidinedione, increases insulin sensitivity in the liver, skeletal muscle, and adipose tissues. Metformin, a biguanide, decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and metformin or who have inadequate glycemic control on a thiazolidinedione alone or metformin alone.
Renal disease or dysfunction (eg, serum creatine levels 1.5 mg/dL or higher in men, 1.4 mg/dL or higher in women, or abnormal CrCl), which may result from acute MI and septicemia; acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma; patients undergoing radiologic studies involving IV administration of iodinated contrast materials; hypersensitivity to any component of the product; patients with established New York Heart Association class III or IV heart failure.
PO Starting dose is based on patient's current regimen of pioglitazone and/or metformin.Patients inadequately controlled on metformin monotherapy
Pioglitazone 15 mg/metformin 500 mg or pioglitazone 15 mg/metformin 850 mg once daily or twice daily, then gradually titrate based on therapeutic response.Patients who initially responded to pioglitazone monotherapy and need additional glycemic control
Pioglitazone 15 mg/metformin 500 mg twice daily or pioglitazone 15 mg/metformin 850 mg once daily, then gradually titrate based on therapeutic response.Patients switching from combination therapy of pioglitazone plus metformin as separate tablets
Pioglitazone 15 mg/metformin 500 mg or pioglitazone 15 mg/metformin 850 mg based on dose of pioglitazone and metformin already being taken.Max dose
Pioglitazone 45 mg/day, metformin 2,550 mg/day.
Store tablets at controlled room temperature (59° to 86°F). Protect from moisture and humidity.
Effect of metformin on lactate metabolism may be potentiated.Cationic drugs (eg, amiloride, digoxin, quinidine)
May increase metformin serum levels by competing for tubular secretion.Cimetidine, nifedipine
Metformin serum levels may be elevated, increasing pharmacologic effects and adverse reactions.CYP3A4 system
Pioglitazone may be a weak inducer of CYP3A4, which may decrease serum levels of other drugs metabolized by this isozyme.Drugs that cause hyperglycemia (eg, calcium channel blockers, corticosteroids, diuretics, estrogens, isoniazid, nicotinic acid, oral contraceptives, phenothiazines, phenytoin, sympathomimetics, thyroid products)
May lead to loss of glycemic control.Furosemide
May increase metformin serum levels; metformin may reduce furosemide levels.Gemfibrozil
Pioglitazone plasma concentrations may be elevated, increasing the risk of hypoglycemia and other adverse reactions (eg, peripheral and pulmonary edema).Insulin
Risk of edema may be increased, even after several months of combined therapy.Iodinated contrast material
May cause acute renal failure and has been associated with lactic acidosis in patients receiving metformin. Withhold metformin therapy at the time of, prior to, and for 48 h after procedures using iodinated contrast material.Rifampin
Pioglitazone plasma concentrations may be reduced, decreasing glycemic control.
Unless otherwise stated, the following adverse reactions were reported with combined use of pioglitazone plus metformin.
Dizziness, headache (5%).
Pharyngitis, tooth disorder (pioglitazone) (5%); macular edema (postmarketing).
Diarrhea, nausea (6%).
Anemia (2% or less).
Decreased serum vitamin B 12 levels (metformin) (7%).
Weight gain (7%).
Myalgia (pioglitazone) (5%).
Upper respiratory tract infection (14%); sinusitis (5%).
Lower limb edema (11%); edema/peripheral edema (6%).
Pioglitazone may cause or exacerbate CHF in some patients. Observe patients carefully for signs or symptoms of heart failure after starting or increasing the dose of pioglitazone. If signs or symptoms develop, manage the heart failure according to the current standards of care. Also, consider discontinuation or dose reduction of pioglitazone. Treatment with pioglitazone is not recommended in patients with symptomatic heart failure.Lactic acidosis
Lactic acidosis can occur because of metformin accumulation during treatment with pioglitazone/metformin; it is fatal in approximately 50% of cases. Lactic acidosis also may occur in association with diabetes mellitus and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis from metformin is usually characterized by metformin plasma levels of more than 5 mcg/mL.
Cases have occurred primarily in diabetic patients with significant renal function impairment, including intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with unstable or acute heart failure who are at risk of hypoperfusion and hypoxemia are at an increased risk of lactic acidosis. The risk of lactic acidosis increases with degree of renal function impairment and age. Risk of lactic acidosis may be reduced by the following: regularly monitoring renal function; using minimum effective dose of metformin; not administering to patients older than 80 yr of age unless measurement of CrCl demonstrates that renal function is not reduced; promptly withholding metformin in presence of any condition associated with hypoxemia, dehydration, or sepsis; avoiding use in patients with clinical or laboratory evidence of hepatic disease; temporarily discontinuing metformin prior to any intravascular radiocontrast study and for any surgical procedure; and having patient avoid excessive alcohol use.
Suspect lactic acidosis in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis.
Lactic acidosis is a medical emergency that must be treated in a hospital setting; discontinue drug and promptly institute general supportive measures. Metformin is dialyzable, and prompt hemodialysis corrects the acidosis and removes accumulated metformin.
Obtain periodic fasting blood glucose and HbA 1c concentrations to monitor therapeutic response. Assess liver enzymes prior to initiation of therapy and periodically thereafter. Monitor all patients for signs and symptoms associated with fluid retention (eg, edema, heart failure). Assess renal function before starting therapy and at least annually thereafter. Monitor renal function more frequently in elderly patients and patients in whom renal function impairment is anticipated. Evaluate hematologic parameters on an annual basis and vitamin B 12 levels at 2- to 3-yr intervals in patients at risk for deficiency. Patients should have regular eye examinations by an ophthalmologist. Promptly refer all patients reporting any visual symptoms to an ophthalmologist.
Category C . Not recommended for use in pregnant patients.
Safety and efficacy not established.
Ensure that initial and maintenance doses are conservative because of potential for reduced renal function; avoid titration to max dose if possible.
Risk of metformin accumulation and lactic acidosis increases with degree of renal function impairment. Patients with serum creatinine levels above ULN for age should not receive metformin-containing products.
Do not initiate therapy in patients with clinical evidence of active liver disease or baseline ALT more than 2.5 × ULN. Initiate or continue therapy in patients with mildly elevated liver enzymes (ALT less than 2.5 × ULN) with caution; discontinue therapy in these patients if ALT increases to more than 3 × ULN and persists, or if patient develops jaundice.
Do not titrate elderly, debilitated, and malnourished patients to the max dose. Do not initiate treatment if a patient exhibits clinical evidence of active liver disease or increased serum transaminase levels at the start of therapy.
Pioglitazone may cause fluid retention. Use with caution in patients with edema or at risk of heart failure.
Increased incidence of bone fracture has been observed in women taking pioglitazone.
Decreases in hemoglobin (2% to 4%) have been reported in patients receiving pioglitazone.
Risk of hypoglycemia increases when used with other oral hypoglycemic agents or insulin; reduction in dose of concomitant agent may be necessary.Type 1 diabetes
Do not use in these patients.
CV shock and other conditions characterized by hypoxemia have been associated with lactic acidosis and also may cause prerenal azotemia. Promptly discontinue therapy if such events occur.
Can lead to acute alteration of renal function and have been associated with metformin-induced lactic acidosis. Temporarily discontinue therapy at time of or prior to the procedure, and withhold for 48 h after the procedure; restart only after renal function has returned to normal.
Consider temporarily withholding therapy and administering insulin in patients who lose glycemic control as result of fever, trauma, infection, or surgery.
Has been reported during postmarketing experience.
Pioglitazone and metformin therapy may result in resumption of ovulation in premenopausal, anovulatory women with insulin resistance. Consider contraceptive measures in such patients.
Temporarily suspend therapy for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids). Do not restart until patient's oral intake has resumed and renal function has been evaluated as normal.
Metformin may interfere with B 12 absorption from the B 12 -intrinsic factor complex.
Dose-related weight gain has been reported. Assess patients who experience unusually rapid increases in weight for fluid accumulation and volume-related events (eg, edema, heart failure).
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