ACTOPLUS MET (pioglitazone and metformin hydrochloride)

ACTOPLUS MET (pioglitazone and metformin hydrochloride)

ACTOPLUS MET (pioglitazone and metformin hydrochloride)

ACTOPLUS MET tablets are a thiazolidinediones and biguanide combination product that contains two oral antidiabetic medications: pioglitazone hydrochloride and metformin hydrochloride.

Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enantiomers.

Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of C19H20N2O3S•HCl and a molecular weight of 392.90 daltons. It is soluble in N,Ndimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a white crystalline powder with a molecular formula of C4H11N5•HCl and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.


ACTOPLUS MET is a thiazolidinedione and biguanide combination product 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.

Important Limitations of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis

Mechanism of Action

ACTOPLUS MET combines two antidiabetic medications with different mechanisms of action to improve glycemic control in adults with type 2 diabetes: pioglitazone, a thiazolidinedione, and metformin hydrochloride, a biguanide. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.

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.

Metformin hydrochloride: Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or healthy subjects [except in specific circumstances, and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Dosage and administration

  • ACTOPLUS MET should be taken with meals to reduce the gastrointestinal side effects associated with metformin.
  • If therapy with a combination tablet containing pioglitazone and metformin is considered appropriate the recommended starting dose is: 15 mg/500 mg twice daily or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability.
  • for patients with New York Heart Association (NYHA) Class I or Class II congestive heart failure: 15 mg/500 mg or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability
  • for patients inadequately controlled on metformin monotherapy: 15 mg/500 mg twice daily or 15 mg/850 mg once or twice daily (depending on the dose of metformin already being taken) and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability
  • for patients inadequately controlled on pioglitazone monotherapy: 15 mg/500 mg twice daily or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability
  • for patients who are changing from combination therapy of pioglitazone plus metformin as separate tablets: ACTOPLUS MET should be taken at doses that are as close as possible to the dose of pioglitazone and metformin already being taken.
  • ACTOPLUS MET may be titrated up to a maximum daily dose of 45 mg of pioglitazone and 2550 mg of metformin.


  • Initiation in patients with established NYHA Class III or IV heart failure.
  • Severe renal impairment (eGFR below 30 mL/min/1.73 m2 )
  • Use in patients with known hypersensitivity to pioglitazone, metformin, or any other component of ACTOPLUS MET.
  • Metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.

Warnings and precautions

Congestive Heart Failure: 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. Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with ACTOPLUS MET should be observed for signs and symptoms of congestive heart failure.

Lactic Acidosis: There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis.

Edema: In controlled clinical trials with pioglitazone, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose related.

Hypoglycemia: Patients receiving ACTOPLUS MET in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia

Hepatic Effects: There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date

Bladder cancer: May increase the risk of bladder cancer. Do not use in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer.

Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health.

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.

Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually.

Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ACTOPLUS MET.

Adverse reactions

Most common adverse reactions (>5%) are upper respiratory tract infection, edema, diarrhea, headache and weight gain.

Drug interactions

  • Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. 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 can potentiate the effect of metformin on lactate metabolism. 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.

Use in specific population

Pregnancy: Limited data with ACTOPLUS MET or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Lactation: There is no information regarding the presence of ACTOPLUS MET or pioglitazone in human milk, the effects on the breastfed infant, or the effects on milk production. 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. Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ACTOPLUS MET and any potential adverse effects on the breastfed infant from ACTOPLUS MET or from the underlying maternal condition.

Females and Males of Reproductive Potential: Discuss the potential for unintended pregnancy with premenopausal women as therapy with ACTOPLUS MET, may result in ovulation in some anovulatory women.

Pediatric Use: Safety and effectiveness of ACTOPLUS MET in pediatric patients have not been established. ACTOPLUS MET is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors.

Renal Impairment: Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. ACTOPLUS MET is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m2

Hepatic Impairment: Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. ACTOPLUS MET is not recommended in patients with hepatic impairment.


Pioglitazone: During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.

In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.

Metformin hydrochloride: Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated metformin from patients in whom metformin overdosage is suspected.


Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity

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