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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…

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…

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 )

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) ] .

U.S. Poison Control: call or text 1-800-222-1222 (free, 24/7). In an emergency call 911. From the FDA label; not medical advice.

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 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 pioglitazone and glimepiride tablets, monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving pioglitazone and glimepiride tablets, 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 pioglitazone and glimepiride tablets, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving pioglitazone and glimepiride tablets, monitor the patient closely for hypoglycemia. Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of pioglitazone and glimepiride tablets glucose-lowering effect. Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of pioglitazone and glimepiride tablets 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, pioglitazone and glimepiride tablets should be administered at least four hours prior to colesevelam [see Clinical Pharmacology (12.3) ] .