Pioglitazone and metformin
Looking up MedlinePlus…
From MedlinePlus, U.S. National Library of Medicine
Boxed warning
WARNING: CONGESTIVE HEART FAILURE and LACTIC ACIDOSIS Congestive Heart Failure Thiazolidinediones, including pioglitazone, which is a component of ACTOPLUS MET ® , cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1) ] . After initiation of ACTOPLUS MET, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If congestive heart failure develops while taking ACTOPLUS MET, consider discontinuation of ACTOPLUS MET or dosage reduction of pioglitazone in ACTOPLUS MET [see Warnings and Precautions (5.1) ] .
ACTOPLUS MET is not recommended in patients with symptomatic heart failure [see Warnings and Precautions (5.1) ] . Initiation of ACTOPLUS MET in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4) , Warnings and Precautions (5.1) ] . Lactic Acidosis Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain.
Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL [see Warnings and Precautions (5.2) ] .
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, hepatic impairment, and mitochondrial diseases [see Warnings and Precautions (5.2) ] .
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the Full Prescribing Information [see Dosage and Administration (2.2) , Contraindications (4) , Warnings and Precautions (5.2) , Drug Interactions (7) , Use in Specific Populations (8.6 , 8.7) ]. If metformin-associated lactic acidosis is suspected, immediately discontinue ACTOPLUS MET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and…
Dosing in kidney impairment
Recommendations for Use in Patients with Renal Impairment Assess renal function prior to initiation of ACTOPLUS MET and periodically thereafter [see Use in Specific Populations ]. ACTOPLUS MET is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min. Initiation of ACTOPLUS MET in patients with an eGFR between 30 to 45 mL/min is not recommended.
In patients taking ACTOPLUS MET whose eGFR later falls below 45 mL/min, assess the benefit and risk of continuing therapy. Discontinue ACTOPLUS MET if the patient’s eGFR later falls below 30 mL/min [see Contraindications , Warnings and Precautions ] .
| Current Regimen | Starting Dosage of ACTOPLUS MET (15 mg of pioglitazone and 850 mg of metformin HCl per tablet)* |
|---|---|
| Not treated with either pioglitazone or metformin HCl | One tablet orally once daily |
| Metformin HCl | One tablet orally once or twice daily. Select a dosage that is as close as possible to the current dosage of metformin HCl |
| Pioglitazone | One tablet orally once daily |
| Pioglitazone and metformin HCl | Select a dosage that is as close as possible to the current dosage of pioglitazone and metformin HCl while not exceeding three tablets orally per day. |
| *For dosage recommendations for patients with renal impairment and/or congestive heart failure, see Dosage and Administration (2.3, 2.4) | |
Dosing in liver impairment
Important Dosage and Administration Information Obtain liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) prior to initiating ACTOPLUS MET [see Warnings and Precautions ] . ACTOPLUS MET contains 15 mg of pioglitazone and 850 mg of metformin hydrochloride (HCl) in each tablet.
Take ACTOPLUS MET with meals to reduce gastrointestinal adverse reactions with metformin [see Adverse Reactions ] . If a dose is missed, do not double the next dose.
Preparation and administration
Recommended Dosage and Administration Recommended Starting Dosage Based on Current Regimen Individualize the starting dosage of ACTOPLUS MET based on the patient's current regimen and the available strength of ACTOPLUS MET (see Table 1 ). [See table below.] Dosage Titration for Additional Glycemic Control Titrate the ACTOPLUS MET dosage gradually, as needed, after assessing therapeutic response and tolerability.
ACTOPLUS MET may be increased to a maximum recommended total daily dosage of three tablets per day (45 mg of pioglitazone and 2,550 mg of metformin HCl). Total daily dosages of 2,550 mg of metformin HCl may be taken in divided doses three times a day to reduce gastrointestinal adverse reactions [see Adverse Reactions ] .
Coadministration with Strong CYP2C8 Inhibitors The maximum recommended dosage of ACTOPLUS MET is one tablet (15 mg of pioglitazone and 850 mg of metformin HCl) once daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions , Clinical Pharmacology ] .
Drug interactions
Check pioglitazone and metformin against a medication listLabel text (10 paragraphs)
Strong CYP2C8 inhibitors (e.g., gemfibrozil): Limit ACTOPLUS MET dose to 15 mg/850 mg daily. ( 7.1 ) CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. ( 7.2 ) Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. ( 7.3 ) 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. ( 7.4 ) Alcohol: Warn patients against excessive alcohol intake. ( 7.5 ) Use of insulin secretagogues or insulin use may increase the risk for hypoglycemia and may require dose reduction.
( 7.6 ) Topiramate may decrease pioglitazone concentrations. ( 7.8 )
7.1 Strong CYP2C8 Inhibitors An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t ½ ) of pioglitazone. Therefore, the maximum recommended dosage of ACTOPLUS MET is 15 mg of pioglitazone and 850 mg of metformin HCl once daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Dosage and Administration (2.3) , Clinical Pharmacology (12.3) ] .
7.2 CYP2C8 Inducers An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with ACTOPLUS MET, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dosage of ACTOPLUS MET (45 mg of pioglitazone and 2,550 mg of metformin HCl) [see Clinical Pharmacology (12.3) ] .
7.3 Carbonic Anhydrase Inhibitors Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with ACTOPLUS MET may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.
7.4 Drugs that Reduce Metformin Clearance Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3) ] . Consider the benefits and risks of concomitant use.
7.5 Alcohol Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving ACTOPLUS MET.
7.6 Insulin Secretagogues or Insulin Coadministration of ACTOPLUS MET with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. If hypoglycemia occurs in a patient coadministered ACTOPLUS MET and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.
7.7 Drugs Affecting Glycemic Control Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving ACTOPLUS MET, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving ACTOPLUS MET, the patient should be observed closely for hypoglycemia.
7.8 Topiramate A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate [see Clinical Pharmacology (12.3) ] . The clinical relevance of this decrease is unknown; however, when ACTOPLUS MET and topiramate are used concomitantly, monitor patients for adequate glycemic control.
Supplement interactions
Dietary supplement interactions
4 noted- Metformin, an antihyperglycemic agent used as first-line treatment for prediabetes and diabetes, might reduce the absorption of vitamin B12 and significantly reduce serum vitamin B12 concentrations.
- Large doses of nicotinic acid can raise blood glucose levels by causing or aggravating insulin resistance and increasing hepatic production of glucose. 5 g/day or more are most likely to increase blood glucose levels in individuals with or without diabetes.
- The results from some studies indicate that chromium supplementation might lower blood glucose levels. Therefore, chromium supplements might have an additive effect with metformin or other antidiabetes medications and thus might increase the risk of hypoglycemia.
- Ashwagandha might also interact with antidiabetes medications, antihypertensives, immunosuppressants, and sedatives.
Contraindications
4 CONTRAINDICATIONS ACTOPLUS MET is contraindicated in patients with: Established NYHA Class III or IV heart failure at the time of ACTOPLUS MET initiation [see Boxed Warning ] . Severe renal impairment (eGFR below 30 mL/min) [see Warnings and Precautions (5.2) ] . A history of serious hypersensitivity to pioglitazone, metformin HCl, or any of the excipients in ACTOPLUS MET. Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.2) ] . In patients with established New York Heart Association (NYHA) Class III or IV heart failure at the time of ACTOPLUS MET initiation [see Boxed Warning ].
( 4 ) In patients with severe renal impairment: (eGFR below 30 mL/min). ( 4 ) In patients with a history of serious hypersensitivity to pioglitazone, metformin HCl, or any of the excipients in ACTOPLUS MET. ( 4 ) In patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis. ( 4 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
LiverTox has no chapter for pioglitazone and metformin. Check the label's hepatic warnings.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary 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 (see Data ). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations ].
In animal reproduction studies, no adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5 and 35 times the 45 mg clinical dose, respectively, based on body surface area. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2 to 6 times, respectively, a 2,000 mg clinical dose, based on body surface area (see Data ).
The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20 to 25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk 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. Data Human Data Published data from postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy.
However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Pioglitazone and Metformin HCl Animal reproduction studies were not conducted with the combined products in ACTOPLUS MET. The following data are based on studies conducted with the individual components of ACTOPLUS MET. Pioglitazone Pioglitazone administered to pregnant rats during organogenesis…
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
Price ladder
Not the price at the counterThese are not what a patient pays at the pharmacy counter. They are what pharmacies, health plans, and government buyers pay, before manufacturer rebates. A patient's cost depends on their insurance (copay, coinsurance, or deductible) or the pharmacy's cash price.