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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ]</span> .
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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .
7.3 Topiramate Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .
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 )
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 pioglitazone and glimepiride tablets, include anaphylaxis, angioedema and Stevens-Johnson Syndrome. Promptly discontinue pioglitazone and glimepiride tablets, 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 pioglitazone and glimepiride tablets and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart pioglitazone and glimepiride tablets 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-phosphate 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 pioglitazone and glimepiride tablets. ( 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 pioglitazone and glimepiride tablets are 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 pioglitazone and glimepiride tablets must be considered <span class="opacity-50 text-xs">[see Boxed Warning , Contraindications (4) and Adverse Reactions (6.1) ]</span> .
5.2 Hypoglycemia Glimepiride All sulfonylureas, including glimepiride, a component of pioglitazone and glimepiride tablets, can cause severe hypoglycemia <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 pioglitazone and glimepiride tablet 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 pioglitazone and glimepiride tablets, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue pioglitazone and glimepiride tablets, 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. The patient should be informed of the potential risks and advantages of glimepiride tablets and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
5.5 Hepatic Effects Pioglitazone There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone-controlled clinical trial database to date <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating pioglitazone and glimepiride tablet therapy. In patients with abnormal liver tests, pioglitazone and glimepiride tablets should be initiated with caution. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), pioglitazone and glimepiride tablet treatment should be interrupted and investigation done to establish the probable cause. Pioglitazone and glimepiride tablets should not be restarted in these patients without another explanation for the liver test abnormalities. Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury and should not be restarted on pioglitazone and glimepiride tablets. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with pioglitazone and glimepiride tablets can be used with caution.
5.6 Urinary Bladder Tumors Pioglitazone Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study <span class="opacity-50 text-xs">[see Nonclinical Toxicology (13.1) ]</span> . In addition, during the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer . After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1.00; [95% CI: 0.59–1.72]). Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among observational studies; some did not find an increased risk of bladder cancer associated with pioglitazone, while others did. A large prospective 10 year observational cohort study conducted in the United States found no statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to pioglitazone, compared to those never exposed to pioglitazone (HR =1.06 [95% CI 0.89-1.26]). A retrospective cohort study conducted with data from the United Kingdom found a statistically significant association between ever exposure to pioglitazone and bladder cancer (HR: 1.63; [95% CI: 1.22–2.19]). Associations between cumulative dose or cumulative duration of exposure to pioglitazone and bladder cancer were not detected in some studies including the 10 year observational study in the U.S., but were in others. Inconsistent findings and limitations inherent in these and other studies preclude conclusive interpretations of the observational data. Pioglitazone may be associated with an increase in the risk of urinary bladder tumors.There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, pioglitazone and glimepiride tablets should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone and glimepiride tablets should be considered in patients with a prior history of bladder cancer.
5.7 Edema Pioglitazone In controlled clinical trials, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose-related <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . In postmarketing experience, reports of new onset or worsening edema have been received. Pioglitazone and glimepiride tablets should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, pioglitazone and glimepiride tablets should be used with caution in patients at risk for congestive heart failure. Patients treated with pioglitazone and glimepiride tablets should be monitored for signs and symptoms of congestive heart failure <span class="opacity-50 text-xs">[see Boxed Warning , Warnings and Precautions (5.1) , and Patient Counseling Information (17) ]</span> .
5.8 Fractures Pioglitazone In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and glimepiride tablets and attention should be given to assessing and maintaining bone health according to current standards of care.
5.9 Hemolytic Anemia Glimepiride Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because pioglitazone and glimepiride tablets contain glimepiride, which belongs to the class of sulfonylurea agents, use caution in patients with G6PD deficiency and consider the use of a nonsulfonylurea alternative. There are also postmarketing reports of hemolytic anemia in patients receiving glimepiride who did not have known G6PD deficiency <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .
5.10 Macular Edema Pioglitazone Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .
5.11 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone and glimepiride tablets.