Dosing & Uses
Dosage Forms & Strengths
Type 2 Diabetes Mellitus
Patients on metformin monotherapy: 15-30 mg/day pioglitazone plus dose of metformin at time of initiating therapy
Patients on pioglitazone monotherapy: 1000-1700 mg metformin/day plus dose of pioglitazone at time of initiating therapy
Not to exceed 45 mg pioglitazone/2550 mg metformin/day
Renal impairment: Do not use
- Baseline ALT <2.5 xULN: Use caution
- Baseline ALT ≥2.5 xULN: Do not administer
- ALT >3 xULN or jaundice after initiating therapy: Discontinue
- Obtain eGFR before starting metformin
- eGFR <30 mL/min/1.73 m²: Contraindicated
- eGFR 30-45 mL/min/1.73 m²: Not recommended to initiate treatment
- Monitor eGFR at least annually or more often for those at risk for renal impairment (eg, elderly)
- If eGFR falls below 45mL/min/1.73 m² while taking metformin, risks and benefits of continuing therapy should be evaluated
- If eGFR falls below 30 mL/min/1.73 m²: while taking metformin, discontinue the drug
Safety and efficacy not established
Type 2 Diabetes Mellitus
Same as adult dosing
Do not administer to patients >80 years before assessing renal function and determined to be normal
Serious - Use Alternative
Significant - Monitor Closely
Lower limb edema (2.9-11.3%)
Upper respiratory infection (12-16)
Weight gain (2.9-6.7%)
Urinary tract infection (5.3-5.8%)
Hepatitis and hepatic enzyme elevations to >3 XUL, including very rare incidences of hepatic failure with and without fatal outcome
Black Box Warnings
Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
Congestive heart failure
- Thiazolidinediones, including pioglitazone and rosiglitazone, cause or exacerbate congestive heart failure in some patients
- Monitor carefully after initiation or dose increases for signs and symptoms of heart failure (including excessive, rapid weight gain; dyspnea; and/or edema); if these signs or symptoms develop, manage heart failure according current standards of care; consider discontinuing or reducing dose
- Not recommended in patients with symptomatic heart failure; initiation of these drugs in patients with established NYHA class III or IV heart failure is contraindicated
- Characterized by elevated blood lactate levels (>5 mmol/L)
- Rare but serious complication that can occur because of metformin accumulation; increased risk with sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure
- Subtle onset with nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, nonspecific abdominal distress)
- Monitor lab for decreased serum pH, increased anion gap, and elevated blood lactate If suspected, discontinue drug and hospitalize patient immediately
- Metformin is highly dialyzable (clearance up to 170 mL/min under good hemodynamic conditions); prompt hemodialysis is recommended to correct the acidosis and to remove accumulated metformin
Severe renal disease: eGFR <30 ml/min/1.73 m²
Acute or chronic metabolic acidosis, including DKA with or without coma
NYHA Class III or IV heart failure
Temporarily discontinue in patients undergoing radiologic exams using iodinated contrast agents
Do not initiate in patients aged ≥80 years CrCl demonstrates that renal function is not reduced because these patients are more susceptible to developing lactic acidosis
Withhold metformin in presence of any condition associated with hypoxemia, dehydration, or sepsis
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia); lactic acidosis is a medical emergency that must be treated in a hospital setting
Pioglitazone may cause fluid retention and cause or exacerbate existing heart failure
Edema; thiazolidinediones, which are peroxisome proliferator-activated receptor (PPAR) gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin
Pioglitazone exerts its antihyperglycemic effect only in presence of insulin; therefore, do not use in type 1 diabetes mellitus or for treatment of diabetic ketoacidosis
May cause hypoglycemia; patients receiving therapy in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia; a reduction in dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia; hypoglycemia can also occur when caloric intake is deficient or when strenuous be necessary to reduce the risk of hypoglycemia exercise is not compensated by caloric supplement; hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs
Rare reports of hepatitis and hepatic enzyme elevations to >3 xULN, including very rare incidences of hepatic failure with and without fatal outcome
In controlled clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, reported; certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels; in these patients, routine serum vitamin B12 measurements at two- to three-year intervals may be useful
Metformin is substantially excreted by kidney, and risk of metformin accumulation and lactic acidosis increases with degree of renal impairment
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis; therapy is not recommended in patients with hepatic impairment
Discuss potential for unintended pregnancy with premenopausal women as therapy with metformin/pioglitazone, may result in ovulation in some anovulatory women
Drug interactions review
- Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis; concomitant use of these drugs with metformin/pioglitazone combination may increase risk for lactic acidosis; consider more frequent monitoring of these patients
- Drugs that are eliminated by renal tubular secretion (e.g., cationic drugs such as cimetidine) have potential for interaction with metformin by competing for common renal tubular transport systems, and may increase accumulation of metformin and risk for lactic acidosis; consider more frequent monitoring of these patients
- Alcohol is known to potentiate the effect of metformin on lactate metabolism; warn patients against excessive alcohol intake while receiving therapy
- If hypoglycemia occurs in a patient coadministered pioglitazone/metformin and an insulin secretagogue (e.g., sulfonylurea), the dose of insulin secretagogue should be reduced; if hypoglycemia occurs in a patient coadministered and insulin, the dose of insulin should be decreased by 10% to 25%; further adjustments to insulin dose should be individualized based on glycemic response
Iodinated contrast imaging procedures
- Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
- Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable
- Bladder cancer
- Pioglitazone may be linked to an increased risk of bladder cancer
- Do not prescribe for patients with active bladder cancer
- Consider benefit:risk ratio before prescribing in patients with a history of bladder cancer
- Instruct patients to contact their physician if signs of bladder cancer observed after initiating therapy (eg, blood or red colored urine, new or worsening urinary urgency, pain on urination)
- Prostate cancer
- 7/22/2015: Compared with nonuse, pioglitazone use was associated with increased risk for prostate cancer (453.3 vs. 449.3 per 100,000 person-years) [JAMA 2015 July 21;314(3):265-277]
- Pancreatic cancer
- 7/22/2015: Compared with nonuse, pioglitazone use was associated with increased risk for pancreatic cancer (81.1 vs. 48.4 per 100,000 person-years) [JAMA 2015 July 21;314(3):265-277]
Pregnancy & Lactation
Pregnancy: Limited data with metformin/pioglitazone or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage; poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications; poorly controlled diabetes increases fetal risk for major birth defects, still birth, and macrosomia related morbidity
Lactation: There is no information regarding the presence of metformin/pioglitazone or pioglitazone in human milk; effects on breastfed infant, or effects on milk production; there is insufficient information on effects of metformin on breastfed infant and no available information on effects of metformin on milk production; developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on the breastfed infant from metformin/pioglitazone or from underlying maternal condition
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Mechanism of Action
Metformin: Biguanide; acts by decreasing endogenous hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization; improves glucose tolerance and lowers both basal and postprandial plasma glucose
Pioglitazone: Thiazolidinedione; insulin-sensitizing agent that acts by enhancing peripheral glucose utilization; decreased insulin resistance in the periphery and in the liver, resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output
Peak plasma time (ACTOplus Met)
- pioglitazone: 1.7-2 hr
- metformin: 2.3-2.5 hr
Peak plasma time (ACTOplus Met XR)
- pioglitazone: 3-3.5 hr
- metformin: 6.9-8 hr
Peak plasma concentration (ACTOplus Met)
- pioglitazone: 659-608 ng/mL
- metformin: 1,203-1,827 ng/mL
Peak plasma concentration (ACTOplus Met XR)
- pioglitazone: 487-866 ng/mL
- metformin: 1,322-1,590 ng/mL
AUC (ACTOplus Met)
- pioglitazone: 5,671-5,984 ng•hr/mL
- metformin: 7,599-11,927 ng•hr/mL
AUC (ACTOplus Met XR)
- pioglitazone: 5,113-9,177 ng•hr/mL
- metformin: 12,705-14,787 ng•hr/mL
Half-Life (ACTOplus Met)
- pioglitazone: 7.2-8.7 hr
- metformin: 6.7-17.6 hr
Half-Life (ACTOplus Met XR)
- pioglitazone: 5.8-7.6 hr
- metformin: 11-11.7 hr
Adding plans allows you to compare formulary status to other drugs in the same class.
To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.
Adding plans allows you to:
- View the formulary and any restrictions for each plan.
- Manage and view all your plans together – even plans in different states.
- Compare formulary status to other drugs in the same class.
- Access your plan list on any device – mobile or desktop.
The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.
|1||This drug is available at the lowest co-pay. Most commonly, these are generic drugs.|
|2||This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.|
|3||This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.|
|4||This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.|
|5||This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.|
|6||This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.|
|NC||NOT COVERED – Drugs that are not covered by the plan.|
Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.