Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate.

Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin. ACTOPLUS MET/ACTOPLUS MET XR  should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ACTOPLUS MET/ACTOPLUS MET XR.

Thiazolidinediones, including pioglitazone, which is a component of ACTOPLUS MET/ACTOPLUS MET XR cause or exacerbate congestive heart failure in some patients.

After initiation of ACTOPLUS MET/ACTOPLUS MET XR, 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 ACTOPLUS MET/ACTOPLUS MET XR must be considered.

ACTOPLUS MET/ACTOPLUS MET XR is not recommended in patients with symptomatic heart failure.

Initiation of ACTOPLUS MET/ACTOPLUS MET XR in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

 Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

If metformin-associated lactic acidosis is suspected, immediately discontinue ACTOPLUS MET/ACTOPLUS MET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

ACTOPLUS MET/ACTOPLUS MET XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m².

Initiation of ACTOPLUS MET/ACTOPLUS MET XR in patients with an eGFR between 30–45 mL/min/1.73 m² is not recommended.

In patients taking ACTOPLUS MET/ACTOPLUS MET XR whose eGFR later falls below 45 mL/min/1.73 m² assess the benefit risk of continuing therapy.

Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin.

Pioglitazone may be associated with an increase in the risk of urinary bladder tumors. There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, ACTOPLUS MET/ACTOPLUS MET XR should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with ACTOPLUS MET/ACTOPLUS MET XR should be considered in patients with a prior history of bladder cancer.

The risk of fracture should be considered in the care of patients, especially female patients, treated with ACTOPLUS MET/ACTOPLUS MET XR and attention should be given to assessing and maintaining bone health according to current standards of care.

Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione.

Reports of decrease to subnormal levels of previously normal serum vitamin B12 levels.

Co-administration of pioglitazone and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold.

An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone.

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with ACTOPLUS MET/ACTOPLUS MET XR may increase the risk for lactic acidosis.

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis.

Discontinue ACTOPLUS MET/ACTOPLUS MET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart ACTOPLUS MET/ACTOPLUS MET XR if renal function is stable.

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving ACTOPLUS MET/ ACTOPLUS MET XR.

Patients receiving ACTOPLUS MET/ACTOPLUS MET XR in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia.

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving ACTOPLUS MET/ACTOPLUS MET XR the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving ACTOPLUS MET/ACTOPLUS MET XR  the patient should be observed closely for hypoglycemia.

Limited data with ACTOPLUS MET/ACTOPLUS MET XR or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Animal studies: delayed parturition and reduced embryo-fetal viability.

Limited published studies report that metformin is present in human milk. Pioglitazone is present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk.

GoToSource:  ACTOPLUS MET 
GoToSource: ACTOPLUS MET XR

• Use in patients under the age of 18. GoToSource

• Post-stroke depression. GoToSource

• Stage I-IV oral cavity or oropharynx cancer. GoToSource

Bladder cancer. GoToSource

Congestive heart failure and pulmonary edema. GoToSource

Weight gain and bone fractures. GoToSource

Strokes in hemodialysis patients. GoToSource

Macular edema (fluid build-up in retina). GoToSource

Vitamin B12 deficiency. GoToSource

Increased alanine aminotransferase levels (indication of liver damage), hypoglycemia (low blood sugar) and lactic acidosis (too much acid in the body). GoToSource

Lawsuits filed for bladder cancer, congestive heart failure, stroke, bone fractures and lactic acidosis.