Pioglitazone And Glimepiride
FDA Drug Information • Also known as: Duetact, Pioglitazone And Glimepiride
- Brand Names
- Duetact, Pioglitazone And Glimepiride
- Drug Class
- Sulfonylurea [EPC]
- Route
- ORAL
- Dosage Form
- TABLET
- Product Type
- HUMAN PRESCRIPTION DRUG
⚠ Boxed Warning (Black Box)
WARNING: CONGESTIVE HEART FAILURE Thiazolidinediones, including pioglitazone, which is a component of pioglitazone and glimepiride tablets, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1) ] . After initiation of pioglitazone and glimepiride tablets 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 heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone and glimepiride tablets must be considered [see Warnings and Precautions (5.1) ] . Pioglitazone and glimepiride tablets are not recommended in patients with symptomatic heart failure [see Warnings and Precautions (5.1) ] . Initiation of pioglitazone and glimepiride tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1) ] . WARNING: CONGESTIVE HEART FAILURE See full prescribing information for complete boxed warning. Thiazolidinediones, including pioglitazone, which is a component of pioglitazone and glimepiride tablets, cause or exacerbate congestive heart failure in some patients. ( 5.1 ) After initiation of pioglitazone and glimepiride tablets, 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 heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone and glimepiride tablets must be considered. ( 5.1 ) Pioglitazone and glimepiride tablets are not recommended in patients with symptomatic heart failure. ( 5.1 ) Initiation of pioglitazone and glimepiride tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated. ( 4 , 5.1 )
Description
11 DESCRIPTION Pioglitazone and glimepiride tablets are a thiazolidinedione and a sulfonylurea combination product that contains two oral antihyperglycemic agents: pioglitazone and glimepiride. The concomitant use of pioglitazone and a sulfonylurea, the class of drugs that includes glimepiride, has been previously approved based on clinical trials in patients with type 2 diabetes inadequately controlled on a sulfonylurea. Additional efficacy and safety information about pioglitazone and glimepiride monotherapies may be found in the prescribing information for each individual drug. Pioglitazone is an oral antidiabetic medication. Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo . No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown: pioglitazone hydrochloride Pioglitazone hydrochloride is an odorless, white crystalline powder that has a molecular formula of C 19 H 20 N 2 O 3 S∙HCl and a molecular weight of 392.90 daltons. It is soluble in N,N -dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. Glimepiride is an oral sulfonylurea chemically identified as 1-[[ p -[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)-urea (C 24 H 34 N 4 O 5 S) with a molecular weight of 490.62. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder and is practically insoluble in water. The structural formula is: glimepiride Pioglitazone and glimepiride tablets are available as a tablet for oral administration containing 30 mg pioglitazone (as the base) with 2 mg glimepiride (30 mg/2 mg) or 30 mg...
What Is Pioglitazone And Glimepiride Used For?
1 INDICATIONS AND USAGE Pioglitazone and glimepiride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and sulfonylurea or who have inadequate glycemic control on a thiazolidinedione alone or a sulfonylurea alone [see Clinical Studies (14) ] . Pioglitazone and glimepiride tablets are a thiazolidinedione and a sulfonylurea combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and glimepiride is appropriate. ( 1 ) Important Limitations of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis. ( 1 ) Important Limitations of Use Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin. Pioglitazone and glimepiride tablets should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. Use caution in patients with liver disease [see Warnings and Precautions (5.5) ].
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Individualize the starting dose of pioglitazone and glimepiride tablets based on the patient's current regimen. ( 2.1 ) May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of pioglitazone 45 mg and glimepiride 8 mg. ( 2.1 ) Pioglitazone and glimepiride tablets should be given in a single dose once daily with meals. ( 2.1 ) Obtain liver tests before starting pioglitazone and glimepiride tablets. If abnormal, use caution when treating with pioglitazone and glimepiride tablets, investigate the probable cause, treat (if possible) and follow appropriately. Monitoring liver tests while on pioglitazone and glimepiride tablets is not recommended in patients without liver disease. ( 5.5 ) 2.1 Recommendations for All Patients Pioglitazone and glimepiride tablets should be taken once daily with the first main meal. Pioglitazone and glimepiride tablets are available as a 30 mg pioglitazone plus 2 mg glimepiride or a 30 mg pioglitazone plus 4 mg glimepiride tablet. If therapy with a combination tablet containing pioglitazone and glimepiride is considered appropriate the recommended starting dose is: 30 mg/2 mg or 30 mg/4 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, for patients inadequately controlled on glimepiride monotherapy: 30 mg/2 mg or 30 mg/4 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, for patients inadequately controlled on pioglitazone monotherapy: 30 mg/2 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, for patients who are changing from combination therapy of pioglitazone plus glimepiride as separate tablets: pioglitazone and glimepiride tablets should be taken at doses that are as close as possible to the dose of pioglitazone and glimepiride already being taken, for patients currently on a different sulfonylurea monotherapy or switching from combination therapy of pioglitazone plus a different sulfonylurea (e.g., glyburide, glipizide, chlorpropamide, tolbutamide, acetohexamide): 30 mg/2 mg once daily and adjusted after assessing adequacy of therapeutic response. Observe for hypoglycemia for one to two weeks due to the potential overlapping drug effect. for patients with systolic dysfunction, the lowest approved dose of pioglitazone and glimepiride tablets should be prescribed only after titration from 15 mg to 30 mg of pioglitazone has been safely tolerated. After initiation of pioglitazone and glimepiride tablets or with dose increase, monitor patients carefully for hypoglycemia and adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions (5.7) ] . Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Congestive Heart Failure [see Boxed Warning and Warnings and Precautions (5.1) ] Hypoglycemia [see Warnings and Precautions (5.2) ] Edema [see Warnings and Precautions (5.7) ] Fractures [see Warnings and Precautions (5.8) ] Hemolytic Anemia [see Warnings and Precautions (5.9) ] Most common adverse reactions (≥5%) are upper respiratory tract infection, accidental injury, and combined edema/peripheral edema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-825-3327 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse events reported in at least 5% of patients in the controlled 16 week clinical studies between placebo plus a sulfonylurea and pioglitazone (15 mg and 30 mg combined) plus sulfonylurea treatment arms were upper respiratory tract infection (15.5% and 16.6%), accidental injury (8.6% and 3.5%), and combined edema/peripheral edema (2.1% and 7.2%), respectively. The incidence and type of adverse events reported in at least 5% of patients in any combined treatment group from the 24 week study comparing pioglitazone 30 mg plus a sulfonylurea and pioglitazone 45 mg plus a sulfonylurea are shown in Table 1; the rate of adverse events resulting in study discontinuation between the two treatment groups was 6% and 9.7%, respectively. Table 1. Adverse Events that Occurred in ≥5% of Patients in Any Treatment Group During the 24 Week Study Adverse Event Pioglitazone 30 mg + Sulfonylurea N=351 n (%) Pioglitazone 45 mg + Sulfonylurea N=351 n (%) Hypoglycemia 47 (13.4) 55 (15.7) Upper Respiratory Tract Infection 43 (12.3) 52 (14.8) Weight Increased 32 (9.1) 47 (13.4) Edema Lower Limb 20 (5.7) 43 (12.3) Headache 25 (7.1) 14 (4.0) Urinary Tract Infection 20 (5.7) 24 (6.8) Diarrhea 21 (6.0) 15 (4.3) Nausea 18 (5.1) 14 (4.0) Pain in Limb 19 (5.4) 14 (4.0) In US double-blind studies, anemia was reported in ≤2% of patients treated with pioglitazone plus a sulfonylurea [see Warnings and Precautions (5.9) ] . Pioglitazone Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with pioglitazone in the PROactive clinical trial. In these trials, over 6000 patients have been treated with pioglitazone for six months or longer, over 4500 patients have been treated with pioglitazone for one year or longer, and over 3000 patients have been treated with pioglitazone for at least two years. In six pooled 16 to 26 week placebo-controlled monotherapy and 16 to 24 week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone than with placebo (3.0%). In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with pioglitazone and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone and 0.6% of patients treated with placebo. Common Adverse Events: 16 to 26 Week Monotherapy Trials: A summary of the incidence and type of common adverse events reported in three pooled 16 to 26 week placebo-controlled monotherapy trials of pioglitazone is provided in Table 2. Terms that are reported represent those that occurred at...
Drug Interactions
7 DRUG INTERACTIONS Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. Limit pioglitazone dose to 15 mg daily. ( 2.3 , 7.1 ) CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. ( 7.2 ) Topiramate may decrease pioglitazone concentrations. ( 7.3 ) Certain medications may affect glucose metabolism, requiring pioglitazone and glimepiride tablet dose adjustment and close monitoring of blood glucose. ( 7.4 ) Miconazole: Severe hypoglycemia can occur when pioglitazone and glimepiride tablets and oral miconazole are used concomitantly. ( 7.5 ) CYP2C9 interactions: Inhibitors and inducers may affect glycemic control by altering glimepiride plasma concentrations. ( 7.6 ) Colesevelam: Coadministration may reduce glimepiride absorption. Pioglitazone and glimepiride tablets should be administered at least 4 hours prior to colesevelam. ( 2.4 , 7.7 ) 7.1 Strong CYP2C8 Inhibitors Pioglitazone 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 dose of pioglitazone is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors. Since the minimum dose of pioglitazone in pioglitazone and glimepiride tablets exceeds 15 mg, patients taking concomitant strong CYP2C8 inhibitors should switch to individual components of pioglitazone and glimepiride tablets, unless the prescribing health care provider determines that the benefit of pioglitazone and glimepiride tablets clearly outweighs the risk of increased pioglitazone exposure [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] . 7.2 CYP2C8 Inducers Pioglitazone 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 pioglitazone, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for pioglitazone [see Clinical Pharmacology (12.3) ] . 7.3 Topiramate Pioglitazone 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 pioglitazone and topiramate are used concomitantly, monitor patients for adequate glycemic control. 7.4 Drugs Affecting Glucose Metabolism Glimepiride A number of medications affect glucose metabolism and may require pioglitazone and glimepiride tablet dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control. The following are examples of medications that may increase the glucose-lowering effect of sulfonylureas including glimepiride, a component of pioglitazone and glimepiride tablets, increasing the susceptibility to...
Contraindications
4 CONTRAINDICATIONS Initiation in patients with established NYHA Class III or IV heart failure [see Boxed Warning ] . Use in patients with known hypersensitivity to pioglitazone, glimepiride or any other component of pioglitazone and glimepiride tablets [see Warnings and Precautions (5.3) ] . Use in patients with known history of an allergic reaction to sulfonamide derivatives. Reported hypersensitivity reactions with glimepiride include cutaneous eruptions with or without pruritus as well as more serious reactions (e.g., anaphylaxis, angioedema, Stevens-Johnson Syndrome, dyspnea) [see Warnings and Precautions (5.3) and Adverse Reactions (6.2) ] Initiation in patients with established New York Heart Association (NYHA) Class III or IV heart failure [see Boxed Warning ] . ( 4 ) Use in patients with known hypersensitivity to pioglitazone, glimepiride or any other component of pioglitazone and glimepiride tablets. ( 4 ) Hypersensitivity to sulfonamide derivatives. ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Limited data with pioglitazone and glimepiride tablets or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are clinical considerations related to fetal and neonatal adverse reactions and drug discontinuation if glimepiride is used during pregnancy. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations ]. 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 the body surface area. Administration of glimepiride to pregnant rats and rabbits during organogenesis induced maternal hypoglycemia and also increased fetal mortality at doses 50 (rats) and 0.1 times (rabbits) the 8 mg clinical dose, respectively, based on body surface area [see Data ] . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% 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. Fetal/Neonatal Adverse Reaction Neonates of women with gestational diabetes, who are treated with sulfonylureas during pregnancy, may be at increased risk for neonatal...
Overdosage
10 OVERDOSAGE Pioglitazone During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms. Glimepiride An overdosage of glimepiride, as with other sulfonylureas, can produce severe hypoglycemia. Mild episodes of hypoglycemia can be treated with oral glucose. Severe hypoglycemic reactions constitute medical emergencies requiring immediate treatment. Severe hypoglycemia with coma, seizure, or neurological impairment can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary because hypoglycemia may recur after apparent clinical recovery [see Warnings and Precautions (5.2) ] .
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Pioglitazone and glimepiride tablets are available in 30 mg pioglitazone plus 2 mg glimepiride or 30 mg pioglitazone plus 4 mg glimepiride tablets as follows: 30 mg/2 mg tablet: white to off-white, round, convex tablets, debossed with 4833G on one side and 30/2 on the other, available in: NDC 66993-821-30 Bottles of 30 30 mg/4 mg tablet: white to off-white, round, convex tablets, debossed with 4833G on one side and 30/4 on the other, available in: NDC 66993-822-30 Bottles of 30 Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed and protect from moisture and humidity.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.