Duetact

Pioglitazone and glimepiride · Tablet · Oral

Prescription (Rx) Peroxisome Proliferator Receptor alpha Agonist Peroxisome Proliferator Receptor gamma Agonist Sulfonylurea

Boxed warning. WARNING: CONGESTIVE HEART FAILURE
• Thiazolidinediones, including pioglitazone, which is a component of DUETACT ® , cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions ( 5.1 )] .
• After initiation of DUETACT 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 DUETACT must be considered [see Warnings and Precautions ( 5.1 )] .
• DUETACT is not recommended in patients with symptomatic heart failure [see Warnings and Precautions ( 5.1 )] .
• Initiation of DUETACT in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications ( 4 ) and Warnings and…

Uses

1 INDICATIONS AND USAGE DUETACT is 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 )] . Important Limitations of Use Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin. DUETACT 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 )] . DUETACT is 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 )

Dosage and administration

• Individualize the starting dose of DUETACT 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 )
• DUETACT should be given in a single dose once daily with meals. ( 2.1 )
• Obtain liver tests before starting DUETACT. If abnormal, use caution when treating with DUETACT, investigate the probable cause, treat (if possible) and follow appropriately. Monitoring liver tests while on DUETACT is not recommended in patients without liver disease. ( 5.5 ) 2.1 Recommendations for All Patients DUETACT should be taken once daily with the first main meal. DUETACT 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: DUETACT 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 DUETACT should be prescribed only after titration from 15 mg to 30 mg of pioglitazone has been safely tolerated. After initiation of DUETACT 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 total bilirubin) should be obtained prior to initiating DUETACT. Routine periodic monitoring of liver tests during treatment with DUETACT is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of DUETACT or who are found to have abnormal liver tests while taking DUETACT should be managed as described under Warnings and Precautions [see Warnings and Precautions ( 5.5 ) and Clinical Pharmacology ( 12.3 )] . 2.2 Concomitant Use with an Insulin Secretagogue or Insulin If hypoglycemia occurs in a patient coadministered DUETACT and an insulin secretagogue, the dose of the insulin secretagogue should be reduced. If hypoglycemia occurs in a patient coadministered DUETACT and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response. 2.3 Concomitant Use with Strong CYP2C8 Inhibitors Coadministration of pioglitazone and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors. If gemfibrozil or other CYP2C8 inhibitors need to co-administered, patients should switch to individual components of DUETACT because the minimum dose of pioglitazone in DUETACT exceeds 15 mg [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] . 2.4 Concomitant Use with Colesevelam When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, DUETACT should be administered at least four hours prior to colesevelam [see Drug Interactions ( 7.7 ) and Clinical Pharmacology ( 12.3 )] .

Dosage forms and strengths

• 30 mg/2 mg tablet: White to off-white, round, convex tablets, debossed with "4833G" on one side and "30/2" on the other
• 30 mg/4 mg tablet: White to off-white, round, convex tablets, debossed with "4833G" on one side and "30/4" on the other
• Tablets: 30 mg pioglitazone/2 mg glimepiride. ( 3 )
• Tablets: 30 mg pioglitazone/4 mg glimepiride. ( 3 )

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 DUETACT [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 DUETACT. ( 4 )
• Hypersensitivity to sulfonamide derivatives. ( 4 )

Warnings and precautions

• Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms. ( 5.1 )
• Hypoglycemia: May be severe. When insulin or an insulin secretagogue is used with pioglitazone, a lower dose of the insulin or insulin secretagogue may be needed to reduce the risk of hypoglycemia. ( 5.2 )
• Hypersensitivity Reactions: Postmarketing reports for glimepiride, a component of DUETACT, include anaphylaxis, angioedema and Stevens-Johnson Syndrome. Promptly discontinue DUETACT, assess for other cases, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. ( 5.3 )
• Potential increased risk of cardiovascular mortality with sulfonylureas: Inform patients of risk, benefits, and treatment alternatives. ( 5.4 )
• Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt DUETACT and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart DUETACT if liver injury is confirmed and no alternate etiology can be found. ( 5.5 )
• Bladder cancer: May increase the risk of bladder cancer. Do not use in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer ( 5.6 )
• Edema: Dose-related edema may occur. ( 5.7 )
• Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. ( 5.8 )
• Hemolytic anemia: Can occur if glucose 6-phophate dehydrogenase (GP6D) deficient. Use with caution in patients with GP6D deficiency. ( 5.9 )
• Macular edema: Postmarketing reports. Recommend regular eye exams in all patients with diabetes according to current standards of care with prompt evaluation for acute visual changes. ( 5.10 )
• Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with DUETACT. ( 5.11 ) 5.1 Congestive Heart Failure Pioglitazone Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when DUETACT is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of DUETACT must be considered [see Boxed Warning, Contraindications ( 4 ) and Adverse Reactions ( 6.1 )] . 5.2 Hypoglycemia Glimepiride All sulfonylureas, including glimepiride, a component of DUETACT, can cause severe hypoglycemia [see Adverse Reactions ( 6.1 )] . The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death. Patients must be educated to recognize and manage hypoglycemia. Use caution when initiating and increasing DUETACT doses in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other antidiabetic medications). Debilitated or malnourished patients and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of glucose-lowering medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested. Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia. 5.3 Hypersensitivity Reactions Glimepiride There have been postmarketing reports of hypersensitivity reactions in patients treated with glimepiride, a component of DUETACT, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue DUETACT, assess for other potential causes for the reaction, and institute alternative treatment for diabetes. 5.4 Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas Glimepiride The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups. UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2.5 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning.

Side effects

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 America, Inc. at 1-877-TAKEDA-7 (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 an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. None of these adverse events were related to the pioglitazone dose. Table 2. Three Pooled 16- to 26-Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence >5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo % of Patients Placebo N=259 Pioglitazone N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Pharyngitis 0.8 5.1 A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 3 . Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. Mean duration of patient follow-up was 34.5 months. Table 3. PROactive Trial: Incidence and Types of Adverse Events Reported in >5% of Patients Treated with Pioglitazone and More Commonly than Placebo % of Patients Placebo N=2633 Pioglitazone N=2605 Hypoglycemia 18.8 27.3 Edema 15.3 26.7 Cardiac Failure 6.1 8.1 Pain in Extremity 5.7 6.4 Back Pain 5.1 5.5 Chest Pain 5.0 5.1 Congestive Heart Failure A summary of the incidence of adverse events related to congestive heart failure is provided in Table 4 for the 16- to 24-week add-on to sulfonylurea trials, for the 16- to 24-week add-on to insulin trials, and for the 16- to 24-week add-on to metformin trials. None of the events were fatal. Table 4.

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 DUETACT dose adjustment and close monitoring of blood glucose ( 7.4 ).
• Miconazole: Severe hypoglycemia can occur when DUETACT 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. DUETACT 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 DUETACT exceeds 15 mg, patients taking concomitant strong CYP2C8 inhibitors should switch to individual components of DUETACT, unless the prescribing health care provider determines that the benefit of DUETACT 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 DUETACT 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 DUETACT 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 DUETACT, increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors. When these medications are administered to a patient receiving DUETACT, monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving DUETACT, monitor the patient closely for worsening glycemic control. The following are examples of medications that may reduce the glucose-lowering effect of sulfonylureas including glimepiride, leading to worsening glycemic control: danazol, glucagon, somatropin, protease inhibitors, atypical antipsychotic medications (e.g., olanzapine and clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid. When these medications are administered to a patient receiving DUETACT, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving DUETACT, monitor the patient closely for hypoglycemia. Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of DUETACT's glucose-lowering effect. Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of DUETACT in an unpredictable fashion. The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine. 7.5 Miconazole Glimepiride A potential interaction between oral miconazole and sulfonylureas leading to severe hypoglycemia has been reported. Whether this interaction also occurs with other dosage forms of miconazole is not known. 7.6 CYP2C9 Interactions Glimepiride There may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers (e.g., rifampin) of CYP2C9. Fluconazole may inhibit the metabolism of glimepiride, causing increased plasma concentrations of glimepiride which may lead to hypoglycemia. Rifampin may induce the metabolism of glimepiride, causing decreased plasma concentrations of glimepiride which may lead to worsening glycemic control. 7.7 Concomitant Administration of Colesevelam Glimepiride Colesevelam can reduce the maximum plasma concentrations and total exposure of glimepiride when the two are coadministered. However, absorption is not reduced when glimepiride is administered four hours prior to colesevelam. Therefore, DUETACT should be administered at least four hours prior to colesevelam [see Clinical Pharmacology ( 12.3 )] .

Use in specific populations

• Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. ( 8.3 )
• Pediatrics: Not recommended for use in pediatric patients. ( 8.4 )
• Geriatric or renally impaired patients: At risk for hypoglycemia with DUETACT. Use caution in dose selection and titration, and monitor closely. ( 8.5 , 8.6 ) 8.1 Pregnancy Risk Summary Limited data with DUETACT 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 intensive care unit admission, and may develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia, lasting 4-10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly. Dose adjustments during pregnancy and the postpartum period Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, DUETACT should be discontinued at least two weeks before expected delivery [see Fetal/Neonatal Adverse Reaction ]. Data Animal Data Pioglitazone and Glimepiride Animal reproduction studies were not conducted with the combined products in DUETACT. The following data are based on studies conducted with the individual components of DUETACT. Pioglitazone Pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg (~5-times the 45 mg clinical dose), but delayed parturition and reduced embryofetal viability at 40 and 80 mg/kg, or ≥9-times the 45 mg clinical dose, by body surface area. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35-times the 45 mg clinical dose), but reduced embryofetal viability at 160 mg/kg, or ~69-times the 45 mg clinical dose, by body surface area. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight occurred in offspring at maternal doses of 10 mg/kg and above or ≥2 times the 45 mg clinical dose, by body surface area. Glimepiride Fetal deaths occurred in rats and rabbits administered glimepiride during the period of organogenesis at doses 50-times (rats) and 0.1-times (rabbits) the 8 mg clinical dose, based on body surface area. This fetotoxicity, observed only at doses inducing maternal hypoglycemia, is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride and has been similarly noted with other sulfonylureas. 8.2 Lactation Risk Summary There is no information regarding the presence of pioglitazone or glimepiride in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone and glimepiride are present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk [see Data ]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DUETACT and any potential adverse effects on the breastfed infant from DUETACT or from the underlying maternal condition. Data During pre- and postnatal studies in rats, glimepiride was present in lactational milk and in serum of nursing rat pups. Offspring exposed to high levels of glimepiride during lactation developed skeletal abnormalities (shortening, thickening and bending of the humerus) during the postnatal period. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some anovulatory women. 8.4 Pediatric Use Safety and effectiveness of DUETACT in pediatric patients have not been established.

Pregnancy

8.1 Pregnancy Risk Summary Limited data with DUETACT 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 intensive care unit admission, and may develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia, lasting 4-10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly. Dose adjustments during pregnancy and the postpartum period Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, DUETACT should be discontinued at least two weeks before expected delivery [see Fetal/Neonatal Adverse Reaction ]. Data Animal Data Pioglitazone and Glimepiride Animal reproduction studies were not conducted with the combined products in DUETACT. The following data are based on studies conducted with the individual components of DUETACT. Pioglitazone Pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg (~5-times the 45 mg clinical dose), but delayed parturition and reduced embryofetal viability at 40 and 80 mg/kg, or ≥9-times the 45 mg clinical dose, by body surface area. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35-times the 45 mg clinical dose), but reduced embryofetal viability at 160 mg/kg, or ~69-times the 45 mg clinical dose, by body surface area. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight occurred in offspring at maternal doses of 10 mg/kg and above or ≥2 times the 45 mg clinical dose, by body surface area. Glimepiride Fetal deaths occurred in rats and rabbits administered glimepiride during the period of organogenesis at doses 50-times (rats) and 0.1-times (rabbits) the 8 mg clinical dose, based on body surface area. This fetotoxicity, observed only at doses inducing maternal hypoglycemia, is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride and has been similarly noted with other sulfonylureas.

Pediatric use

8.4 Pediatric Use Safety and effectiveness of DUETACT in pediatric patients have not been established. DUETACT is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors [see Warnings and Precautions ( 5.1 , 5.6 , 5.7 , 5.8 )]. Glimepiride The pharmacokinetics, efficacy and safety of glimepiride have been evaluated in pediatric patients with type 2 diabetes as described below. Glimepiride is not recommended in pediatric patients because of its adverse effects on body weight and hypoglycemia. The pharmacokinetics of a 1 mg single dose of glimepiride was evaluated in 30 patients with type 2 diabetes (male = 7; female = 23) between ages 10 and 17 years. The mean (±SD) AUC (0-last) (339±203 ng
• hr/mL), C max (102±48 ng/mL) and t 1/2 (3.1±1.7 hours) for glimepiride were comparable to historical data from adults (AUC (0-last) 315±96 ng
• hr/mL, C max 103±34 ng/mL and t 1/2 5.3±4.1 hours). The safety and efficacy of glimepiride in pediatric patients was evaluated in a single-blind, 24-week trial that randomized 272 patients (8 to 17 years of age) with type 2 diabetes to glimepiride (n=135) or metformin (n=137). Both treatment-naïve patients (those treated with only diet and exercise for at least two weeks prior to randomization) and previously treated patients (those previously treated or currently treated with other oral antidiabetic medications for at least three months) were eligible to participate. Patients who were receiving oral antidiabetic agents at the time of study entry discontinued these medications before randomization without a washout period. Glimepiride was initiated at 1 mg, and then titrated up to 2, 4 or 8 mg (mean last dose 4 mg) through Week 12, targeting a self monitored fasting fingerstick blood glucose <126 mg/dL. Metformin was initiated at 500 mg twice daily and titrated at Week 12 up to 1000 mg twice daily (mean last dose 1365 mg). After 24 weeks, the overall mean treatment difference in HbA1c between glimepiride and metformin was 0.2%, favoring metformin (95% confidence interval -0.3% to +0.6%). Based on these results, the trial did not meet its primary objective of showing a similar reduction in HbA1c with glimepiride compared to metformin. The profile of adverse reactions in pediatric patients treated with glimepiride was similar to that observed in adults. Hypoglycemic events documented by blood glucose values <36 mg/dL were observed in 4% of pediatric patients treated with glimepiride and in 1% of pediatric patients treated with metformin. One patient in each treatment group experienced a severe hypoglycemic episode (severity was determined by the investigator based on observed signs and symptoms).

Geriatric use

8.5 Geriatric Use To minimize the risk of hypoglycemia, the initial dosing, dose increments, and maintenance dosage of DUETACT should be conservative. During initiation of DUETACT therapy and any subsequent dose adjustments, geriatric patients should be observed carefully for hypoglycemia. Pioglitazone A total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16- to 26-week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16- to 24-week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥65 years old and 22 (2.1%) were ≥75 years old. In PROactive, 1068 patients (41.0%) treated with pioglitazone were ≥65 years old and 42 (1.6%) were ≥75 years old. In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients [see Clinical Pharmacology ( 12.3 )] . Although clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥75 years old. Glimepiride In clinical trials of glimepiride, 1053 of 3491 patients (30%) were ≥65 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. There were no significant differences in glimepiride pharmacokinetics between patients with type 2 diabetes ≤65 years (n=49) and those >65 years (n=42) [see Clinical Pharmacology ( 12.3 )] . Glimepiride is substantially excreted by the kidney. Elderly patients are more likely to have renal impairment. In addition, hypoglycemia may be difficult to recognize in the elderly [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.2 )] . Use caution when initiating DUETACT and increasing the dose of DUETACT in this patient population.

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 )] .

Description

11 DESCRIPTION DUETACT 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 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: DUETACT is 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 pioglitazone (as the base) with 4 mg glimepiride (30 mg/4 mg) formulated with the following excipients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, hydroxypropyl cellulose NF, polysorbate 80 NF, and microcrystalline cellulose NF. pio-chem structure.jpg glim-chem structure.jpg

Mechanism of action

12.1 Mechanism of Action DUETACT combines 2 antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: pioglitazone, a member of the thiazolidinedione class, and glimepiride, a member of the sulfonylurea class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas sulfonylureas are insulin secretagogues that act primarily by stimulating release of insulin from functioning pancreatic beta cells. Pioglitazone Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Glimepiride Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic beta cells. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.

How supplied

16 HOW SUPPLIED/STORAGE AND HANDLING DUETACT is 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 64764-302-30 Bottles of 30 NDC 64764-302-90 Bottles of 90 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 64764-304-30 Bottles of 30 NDC 64764-304-90 Bottles of 90 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.

Patient information

See FDA-approved patient labeling (Medication Guide) .
• Inform patients that DUETACT is not recommended for patients with symptoms of heart failure.
• Inform patients that patients with severe heart failure (NYHA Class III or IV) cannot start DUETACT as the risks exceed the benefits in such patients.
• It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients should also be informed of the potential risks and advantages of DUETACT and of alternative modes of therapy.
• Tell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.
• Prior to initiation of DUETACT therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members [see Warnings and Precautions ( 5.2 )] . Combination therapy of DUETACT with other antihyperglycemic agents may also cause hypoglycemia.
• Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on DUETACT should immediately report these symptoms to a physician.
• Tell patients to promptly stop taking DUETACT and seek immediate medical advice if there is unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine as these symptoms may be due to hepatotoxicity.
• Inform female patients that treatment with pioglitazone, like other thiazolidinediones may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation [see Use in Specific Populations (8.3) ] .
• Patients should be told to take a single dose of DUETACT once daily with the first main meal and instructed that any change in dosing should be made only if directed by their physician [see Dosage and Administration ( 2 )] . Distributed by: Takeda Pharmaceuticals America, Inc. Cambridge, MA 02142 DUETACT is a registered trademark of Takeda Pharmaceutical Company Limited. © 2025 Takeda Pharmaceuticals America, Inc. All rights reserved. DTA007 R17

Label text from the FDA structured product label by Takeda Pharmaceuticals America, Inc. (revised Mar 27, 2025). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Pioglitazone Hydrochloride in 2 products
Glimepiride in 2 products

Duetact NDC products (2)

NDC	Strength & form	Labeler	Type
64764-302	Pioglitazone Hydrochloride 30 mg/1; Glimepiride 2 mg/1 Tablet	Takeda Pharmaceuticals America, Inc.	NDA
64764-304	Pioglitazone Hydrochloride 30 mg/1; Glimepiride 4 mg/1 Tablet	Takeda Pharmaceuticals America, Inc.	NDA

Frequently asked questions

What is Duetact used for?

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Who makes Duetact?

Duetact is listed by 1 labeler in the FDA NDC directory, including Takeda Pharmaceuticals America, Inc..