metformin/pioglitazone (Rx)

>10%

Lower limb edema (2.9-11.3%)

Upper respiratory infection (12-16)

1-10%

Weight gain (2.9-6.7%)

Diarrhea (4.8-5.8%)

Nausea (3.6-5.8%)

Urinary tract infection (5.3-5.8%)

Dizziness (4.8-5.4%)

Headache (4.6-5.3%)

Sinusitis (4.4-5%)

Edema (3%)

Postmarketing Reports

Hepatitis and hepatic enzyme elevations to >3 XUL, including very rare incidences of hepatic failure with and without fatal outcome

Cholestatic, hepatocellular, and mixed hepatocellular liver injury

Contraindications

Hypersensitivity

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

Cautions

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

Cancer risk

• 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: 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

Pregnancy Categories

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

Pharmacokinetics

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