Metformin-Pioglitazone

Metformin-Pioglitazone is a combination medication used for the treatment of type 2 diabetes mellitus.

• Metformin-Pioglitazone is available under the following different brand names: ACTOplus Met, ACTOplus Met XR

Common side effects of Metformin-Pioglitazone include:

• headache,
• nausea,
• vomiting,
• stomach upset,
• diarrhea,
• weakness,
• sore throat,
• muscle pain,
• weight gain,
• tooth problems,
• a metallic taste in the mouth, or
• sneezing, runny nose, cough, or other signs of a cold.

Serious side effects of Metformin-Pioglitazone include:

• hives,
• difficulty breathing,
• swelling of the face, lips, tongue, or throat,
• unusual muscle pain,
• feeling cold,
• dizziness,
• lightheadedness,
• tiredness,
• weakness,
• stomach pain,
• vomiting,
• slow or irregular heart rate,
• pink or red urine,
• painful or difficult urination,
• new or worsening urge to urinate,
• changes in the vision,
• swelling,
• rapid weight gain,
• shortness of breath,
• loss of appetite,
• nausea,
• vomiting,
• stomach pain,
• tiredness,
• dark urine,
• yellowing of the skin or eyes (jaundice),
• pale skin,
• unusual tiredness,
• shortness of breath, 
• cold hands and feet,
• new or worsening vision problems (such as blurred vision),
• bone fracture,
• reddish-colored urine,
• urgent need to urinate, or
• pain while urinating.

Rare side effects of Metformin-Pioglitazone include:

• none

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors;
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out. 

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Tablet

• 500 mg/15 mg
• 850 mg/15 mg

Tablet, extended-release

• 1,000 mg/15 mg
• 1,000 mg/30 mg

Type 2 Diabetes Mellitus

Adult dosage

• Patients on metformin monotherapy: 15-30 mg/day pioglitazone plus a dose of metformin at the time of initiating therapy
• Patients on pioglitazone monotherapy: 1000-1700 mg metformin/day plus a dose of pioglitazone at the time of initiating therapy
• Not to exceed 45 mg pioglitazone/2550 mg metformin/day

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Metformin-Pioglitazone has severe interactions with no other drugs.
• Metformin-Pioglitazone has serious interactions with the following drugs:
  • baricitinib
  • contrast media (iodinated)
  • eluxadoline
  • ethanol
  • gemfibrozil
  • ioversol
  • methylene blue
  • pacritinib
  • ranolazine
  • tucatinib
• Metformin-Pioglitazone has moderate interactions with atleast 248 other drugs.
• Metformin-Pioglitazone has minor interactions with at least 149 other drugs.

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all your products. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, or if you have health questions or concerns.

Contraindications

• Hypersensitivity
• Severe renal disease: eGFR less than 30 ml/min/1.73 m²
• Acute or chronic metabolic acidosis, including DKA with or without coma
• NYHA Class III or IV heart failure

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Metformin-Pioglitazone?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Metformin-Pioglitazone?”

Cautions

• Temporarily discontinue in patients undergoing radiologic exams using iodinated contrast agents
• Do not initiate in patients aged above 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 the 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 more than 3 times the ULN, 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 the kidney, and the risk of metformin accumulation and lactic acidosis increases with the 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 the 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 the 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 the potential for interaction with metformin by competing for common renal tubular transport systems, and may increase the 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 with 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 iodinated 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 are 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 and 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 the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications; poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity
• Lactation
  • There is no information regarding the presence of Metformin-Pioglitazone or pioglitazone in human milk; its effects on breastfed infants, or its effects on milk production; 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; 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 an underlying maternal condition