Brand and Other Names:ACTOplus Met, ACTOplus Met XR
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
Rare reports of hepatitis and hepatic enzyme elevations to >3 xULN, including very rare incidences of hepatic failure with and without fatal outcome
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
- 5-year interim results of a 10-year cohort study suggest that pioglitazone use >12 months increases the relative risk of developing bladder cancer in any given year by 40%, an increase from ~7 cases in 10,000 to ~10 cases in 10,000
- Greatest risk was shown in patients with long-term use and the highest cumulative doses
- FDA recommendations include not prescribing pioglitazone for patients with active bladder cancer and cautious use in patients with a history of bladder cancer 7/22/2015: A prospective study found that during ~7 years' follow-up, the rate of incident bladder cancer was higher in patients who had ever used pioglitazone than nonusers (89.8 vs. 75.9 per 100,000 person-years), but the difference was not significant after adjustment for potential confounders [JAMA 2015 July 21;314(3):265-277]
- 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 Category: C
Lactation: not known if crosses into breast milk, avoid using in nursing women
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
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