VA Class:HS502

ATC Class:A10BG02

AHFS Class:

• Thiazolidinediones 68:20.28

Generic Name(s):

• Rosiglitazone Maleate

Chemical Name:

• (±)-5-[ p -[2-(methyl-2-pyridylamino)ethoxy]benzyl]-2,4-thiazolidinedione maleate

Molecular Formula:

• C₁₈H₁₉N₃O₃S

Rosiglitazone is a thiazolidinedione (glitazone) antidiabetic agent that is structurally and pharmacologically related to pioglitazone and troglitazone.1,2,3,4,6,7,9,10,11,13,14,16,20,30

Type 2 Diabetes Mellitus

Rosiglitazone is used as monotherapy or in combination with a sulfonylurea, metformin hydrochloride, or a sulfonylurea and metformin as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1,30,106,111,112,121,122

Rosiglitazone may be added to therapy with the fixed combination of glyburide and metformin hydrochloride in patients whose hyperglycemia is not adequately controlled on therapy with the fixed combination.111 (See Concomitant Glyburide and Metformin Therapy under Dosage and Administration: Dosage, in Glyburide 68:20.20.)

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).698,704,705 (See Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.) In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, sodium-glucose cotransporter 2 [SGLT2] inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698,704 Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another drug) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.698,704 In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic drug classes with complementary mechanisms of action.698

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.698,704 Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA_1c by approximately 0.7-1%.704 In addition, early initiation of combination therapy may help more rapidly attain glycemic goals and extend the time to treatment failure.704

Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.698,699,704,705,706 When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.698,704 While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698,704 For additional information regarding the initiation of insulin therapy in patients with diabetes mellitus, see Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

Rosiglitazone Monotherapy

Efficacy of rosiglitazone as monotherapy for the management of type 2 diabetes mellitus was established in 6 controlled studies of 8-52 weeks' duration.1 Rosiglitazone improved glycemic control as measured by fasting glucose and HbA_1c concentrations.1,30 Some evidence suggests that rosiglitazone has a more durable glycemic effect than sulfonylureas or metformin.126,151 In a long-term (4-6 years' duration) randomized, controlled clinical trial (A Diabetes Outcome Progression Trial [ADOPT]) evaluating the duration of glycemic control after initiation of monotherapy with rosiglitazone, metformin, or glyburide, the cumulative incidence of treatment failure (i.e., defined as confirmed fasting plasma glucose concentrations exceeding 180 mg/dL on consecutive testing after at least 6 weeks of treatment at the maximum dictated or tolerated dosage of the study drug) at 5 years was 15, 21, and 34%, respectively; this represents a risk reduction with rosiglitazone monotherapy of 32% or 63% compared with metformin or glyburide monotherapy, respectively.1,126,154 However, the use of fasting glucose concentrations as a measure of treatment failure rather than HbA_1c concentration, which correlates more closely with diabetic complications, has been criticized; also, differences among the treatment groups in mean HbA_1c concentration at 4 years were less pronounced, particularly between rosiglitazone and metformin.154

The manufacturer states that rosiglitazone should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.1,146

Combination Therapy

Data from a number of comparative trials evaluating combination therapy with rosiglitazone and metformin or a sulfonylurea agent indicate that such combination therapy may result in an additive effect on glycemic control.1,106 Efficacy of the combination of rosiglitazone and metformin in patients whose type 2 diabetes mellitus was inadequately controlled with metformin alone was established in several controlled studies of 26 weeks' duration in which combined therapy improved glycemic control without affecting serum insulin concentrations.1,30,106,112 In patients inadequately controlled with sulfonylurea (e.g., glyburide, glipizide, glimepiride) monotherapy, the combination of rosiglitazone and a sulfonylurea reduced fasting glucose and HbA_1c concentrations compared with monotherapy with a sulfonylurea alone.1,106

Substantial improvements in fasting plasma glucose and HbA_1c concentrations have been observed in patients receiving concurrent rosiglitazone and metformin therapy compared with those receiving metformin alone.112 In a dose-ranging trial evaluating rosiglitazone 4 or 8 mg as add-on therapy to the maximum daily dosage of metformin hydrochloride, 28.1% of patients receiving the higher dosage of rosiglitazone concurrently with metformin achieved HbA_1c values not exceeding 7%.112

In patients inadequately controlled with sulfonylurea (e.g., glyburide, glipizide, glimepiride) monotherapy, the combination of rosiglitazone and a sulfonylurea reduced fasting glucose and HbA_1c concentrations compared with monotherapy with a sulfonylurea alone.1,106 In a 2-year study in geriatric patients (59-89 years of age) who were inadequately controlled on glipizide at half the maximum recommended dosage (10 mg twice daily), the addition of rosiglitazone (4-8 mg daily) was more effective in preventing loss of glycemic control (defined as fasting plasma glucose concentrations of at least 180 mg/dL, the primary clinical end point) than continued upward titration of glipizide (maximum of 20 mg twice daily).1,120

General

Following initiation of rosiglitazone therapy or dosage increases, patients should be monitored for adverse effects related to fluid retention.1 (See Congestive Heart Failure under Warnings/Precautions: Warnings, in Cautions.) Fasting blood glucose (FPG) and glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) concentrations should be monitored periodically to determine the patient's response to therapy.1,146

Following initiation of rosiglitazone therapy or dosage increases, sufficient time should be allowed to assess therapeutic response to rosiglitazone (8-12 weeks using FPG concentrations).1

Administration

Rosiglitazone maleate is administered orally once daily or in divided doses twice daily,1 without regard to meals.1,25,146 If the patient misses a dose of rosiglitazone, the missed dose should be taken as soon as it is remembered.1,146 If the missed dose is remembered at the time of the next dose, the regularly scheduled dose should be taken; a double dose should not be taken to make up for the missed dose.1,146

Dosage

Type 2 Diabetes Mellitus

Dosage of rosiglitazone maleate is expressed in terms of the base.1

Rosiglitazone Monotherapy

The recommended initial dosage of rosiglitazone is 4 mg once daily or 2 mg twice daily.1,146 If the response is inadequate after 8-12 weeks, dosage may be increased to 8 mg daily as a single dose or 2 divided doses daily.1 The maximum recommended dosage is 8 mg daily; studies suggest no additional benefit from 12-mg daily dosages.1,30

Combination Therapy

A thiazolidinedione such as rosiglitazone may be added to the antidiabetic regimen in patients who have inadequate glycemic control with repaglinide monotherapy.115 Conversely, if glycemic control with thiazolidinedione monotherapy is inadequate, repaglinide may be added to the antidiabetic regimen.115 (See Type 2 Diabetes Mellitus under Dosage and Administration: Dosage, in Repaglinide 68:20.16.) To minimize the risk of hypoglycemia, the dosage of each agent should be carefully adjusted to determine the minimal dosage required to achieve glycemic control.115

For patients who have inadequate glycemic control on the fixed combination of glyburide and metformin hydrochloride, a thiazolidinedione such as rosiglitazone may be added at its recommended initial dosage and the dosage of the fixed combination may be continued unchanged.111 In patients requiring further glycemic control, the dosage of rosiglitazone may be titrated upward according to the manufacturer's recommendations. 111 Triple therapy with glyburide, metformin hydrochloride, and a thiazolidinedione may increase the potential for hypoglycemia at any time of day. 111 If hypoglycemia develops with such triple therapy, consideration should be given to reducing the dosage of the glyburide component; adjustment of the dosage of the other components of the antidiabetic regimen also should be considered as clinically indicated.111

Special Populations

Rosiglitazone maleate should be initiated (or continued) with caution in patients with mild hepatic enzyme elevations (ALT not exceeding 2.5 times the upper limit of normal) but no evidence of active liver disease.1 Therapy with rosiglitazone should not be initiated in patients with baseline ALT concentrations exceeding 3 times the upper limit of normal.1 (See Hepatic Effects under Warnings/Precautions: General Precautions, in Cautions.)

Adjustment of rosiglitazone dosage is not necessary for patients with renal impairment nor for geriatric patients.1

Contraindications

Initiation of therapy with rosiglitazone is contraindicated in patients with New York Heart Association (NYHA) class III or IV heart failure.1,128,157 (See Congestive Heart Failure under Warnings/Precautions: Warnings, in Cautions.)

Rosiglitazone is contraindicated in patients with a history of hypersensitivity to the drug or to any ingredient in the formulation.1

Warnings/Precautions

Warnings

Congestive Heart Failure

Thiazolidinediones, including rosiglitazone, alone or in combination with other antidiabetic agents, can cause fluid retention and may lead to or exacerbate congestive heart failure (CHF).1,116,117,128,141,143 Use of thiazolidinediones is associated with an approximately twofold increased risk of CHF.131,143,148,151,155 (See Edema under Warnings/Precautions: General Precautions, in Cautions.) Patients should be observed for signs and symptoms of CHF (e.g., dyspnea, rapid weight gain, edema, unexplained cough or fatigue), especially during initiation of therapy and dosage titration.1,117,128 If signs and symptoms of CHF develop, the disorder should be managed according to current standards of care.1,117,128 In addition, a decrease in the dosage of rosiglitazone or discontinuance of the drug should be considered.1

Initiation of therapy with rosiglitazone is contraindicated in patients with NYHA class III or IV heart failure.1,128,157 Patients with NYHA class III or IV cardiac status with or without CHF or with acute coronary syndromes were not studied in clinical trials of rosiglitazone; use of rosiglitazone is not recommended in these patients.1,113,149 If an acute coronary event occurs, the manufacturer states that discontinuance of rosiglitazone should be considered during the acute phase of a coronary event, as such patients are at risk for development of CHF.1 In addition, use of rosiglitazone is not recommended in patients with symptomatic heart failure.1,150 Caution should be exercised in patients with edema and in those who are at risk for CHF.1,117,148 Thiazolidinedione therapy should not be initiated in hospitalized patients with diabetes mellitus because of the delayed onset of action and because possible drug-related increases in vascular volume and CHF may complicate care of patients with hemodynamic changes induced by coexisting conditions or in-hospital interventions.114

Findings from a meta-analysis of randomized controlled studies that assessed the risk of development of CHF and death from cardiovascular causes in patients receiving thiazolidinediones indicate that the risk of CHF is higher in patients receiving thiazolidinediones (relative risk of 1.72; 95% confidence interval: 1.21-2.42) than in controls (individuals receiving other antidiabetic agents or placebo).143 The relative risk for CHF was increased across a wide background of cardiovascular risk (i.e., patients with prediabetes, with type 2 diabetes mellitus without cardiovascular disease, with type 2 diabetes mellitus and cardiovascular disease other than CHF, or with type 2 diabetes mellitus and CHF [NYHA class I or II] and ejection fraction less than 40%).143 In contrast to the increased risk for CHF observed in thiazolidinedione-treated patients, the risk of cardiovascular death was not increased in patients receiving these agents.143

In a placebo-controlled echocardiographic study in patients with type 2 diabetes mellitus and NYHA class I or II heart failure receiving rosiglitazone in addition to other antidiabetic and CHF therapy, an increased incidence of adverse cardiovascular events (e.g., edema, need for additional CHF therapy) was reported in patients receiving rosiglitazone compared with patients receiving placebo.1,128,142 Changes in the left ventricular ejection fraction from baseline did not differ among rosiglitazone- or placebo-treated patients.1,128,142 In a long-term, cardiovascular outcomes trial in patients with type 2 diabetes mellitus, heart failure was reported in 2.7% of patients receiving rosiglitazone compared with 1.3% of those receiving active control (metformin plus a sulfonylurea).1

An increased incidence of CHF has been observed in a number of clinical trials (duration of 16-26 weeks) in patients receiving rosiglitazone as add-on therapy to insulin compared with that in patients receiving insulin monotherapy.1,128 These trials included patients with long-standing diabetes mellitus (median duration: 12 years) and a high prevalence of preexisting medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and CHF.1 The incidence of emergent symptomatic heart failure was at least twofold higher with concurrent rosiglitazone and insulin therapy compared with that observed with insulin therapy alone.1 The manufacturer states that concurrent administration of rosiglitazone and insulin therapy is not recommended.1

Some observational studies have indicated a substantially increased risk of heart failure requiring hospitalization in geriatric patients 65 years of age or older receiving rosiglitazone compared with another thiazolidinedione antidiabetic agent (pioglitazone).1

General Precautions

Major Adverse Cardiovascular Events

The cardiovascular safety of rosiglitazone has been an area of ongoing concern and study.129,130,131,132,133,134,148,151,155,205,206,207,209,210,211 Findings from several meta-analyses of principally short-term trials and observational studies suggested that rosiglitazone may be associated with an increased risk of myocardial infarction (MI) and other adverse cardiovascular events.1,128,130,132,144,148,151,155,217,220 However, although some uncertainty remains regarding the cardiovascular risk of rosiglitazone, FDA states that concerns have been substantially reduced in light of the readjudicated findings of a dedicated cardiovascular outcomes trial (the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes [RECORD]).220 FDA has therefore removed previous prescribing and dispensing restrictions for the drug.220,223 Despite some limitations, the RECORD trial is considered to represent a higher level of evidence regarding cardiovascular risk than meta-analyses and observational studies, and therefore provides some reassurance that rosiglitazone does not increase the risk of MI or other adverse cardiovascular effects compared with other antidiabetic agents.223

In a meta-analysis of 52 randomized, double-blind trials (mean duration: 6 months), a substantially increased risk of MI was observed with rosiglitazone versus placebo; in addition, major adverse cardiovascular events (MACE) occurred more frequently in patients receiving rosiglitazone than in those receiving comparator agents, although the difference was not statistically significant.1,217 As a result of these findings, the US Food and Drug Administration (FDA) restricted use of rosiglitazone in 2010 to patients who were unable to achieve glycemic control with other antidiabetic agents.205,206,215,220 However, evidence regarding the cardiovascular risk of rosiglitazone has been conflicting, and the findings observed in previous meta-analyses have not been confirmed in long-term (greater than 3 years' duration), prospective randomized studies.1,220 These studies, which include the RECORD study, generally have found no evidence of an increased risk of mortality or MACE with rosiglitazone compared with metformin and/or a sulfonylurea.1 In the RECORD study, rosiglitazone was noninferior to the combination of metformin and a sulfonylurea with respect to the primary composite end point of cardiovascular hospitalization or cardiovascular death.1,213 During the course of FDA's original review of the RECORD study, important questions arose about potential bias in the identification of cardiovascular events, prompting FDA to commission outside experts to perform an independent readjudication of the data.220,221,222 Results of this comprehensive reanalysis confirmed the original findings that failed to show an increased risk of MI with rosiglitazone versus metformin and a sulfonylurea.1,221 While some component end points appeared to favor rosiglitazone (i.e., cardiovascular deaths, nonfatal strokes, all-cause mortality) or metformin/sulfonylurea (i.e., nonfatal MI), these findings were not statistically significant.220 Results of 2 other long-term, prospective randomized studies also showed no statistically significant differences in MACE or its individual components between rosiglitazone and placebo (the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication [DREAM] trial in patients with impaired glucose tolerance) or between rosiglitazone and metformin or a sulfonylurea (the Diabetes Outcome Progression Trial [ADOPT] in patients with type 2 diabetes mellitus who were initiating oral antidiabetic monotherapy).1

Edema

Fluid retention can occur and may lead to or exacerbate heart failure in patients receiving a thiazolidinedione, including rosiglitazone, alone or in combination with other antidiabetic agents, including insulin.1,13,116,117,128 Patients with ongoing edema are more likely to have adverse events associated with edema if therapy with rosiglitazone in combination with insulin is initiated.1 Diuretic therapy may be necessary for management of fluid retention.117 Weight gain possibly associated with fluid retention and fat accumulation has been observed during therapy with rosiglitazone alone or in combination with other antidiabetic agents (e.g., metformin, sulfonylureas, insulin).1,117 Caution should be exercised in patients with edema and those at risk for CHF.1,117,148 (See Congestive Heart Failure under Warnings/Precautions: Warnings, in Cautions.)

All patients receiving thiazolidinedione therapy (e.g., rosiglitazone, pioglitazone) should be advised to monitor for weight gain and edema.1,117 Any patient developing edema within the first few months of therapy should be evaluated for possible CHF.117 Other potential causes of edema should be excluded.117

Musculoskeletal Effects

Thiazolidinedione use is associated with bone loss and fractures in women and possibly in men with type 2 diabetes mellitus.1,125,126,127,132,139,145,147,151 In long-term comparative clinical trials in patients with type 2 diabetes mellitus, the incidence of bone fracture was increased in patients (particularly women) receiving rosiglitazone versus comparator agents (glyburide and/or metformin).1,125,126,147 Such effects were noted after the first year of treatment and persisted throughout the study.1 The majority of fractures observed in patients taking thiazolidinediones were in a distal upper limb (i.e., forearm, hand, wrist) or distal lower limb (i.e., foot, ankle, fibula, tibia).1,125,127,147 In an observational study in the United Kingdom in men and women (mean age: 60.7 years) with diabetes mellitus, use of pioglitazone or rosiglitazone for approximately 12-18 months (as estimated from prescription records) was associated with a twofold to threefold increase in fractures, particularly of the hip and wrist.145 The overall risk of fracture was similar among men and women and was independent of body mass index, comorbid conditions, diabetic complications, duration of diabetes mellitus, and use of other oral antidiabetic drugs.145

Risk of fractures should be considered when initiating or continuing thiazolidinedione therapy in female patients with type 2 diabetes mellitus.1,125,127,147 Bone health should be assessed and maintained according to current standards of care.1,125,147 Although increased risk of fracture may also apply to men, the risk appears to be higher among women than men.1

Ovulatory Effects

Risk for pregnancy unless contraceptive measures initiated; anovulatory premenopausal women with insulin resistance may resume ovulation during therapy.1 The frequency of resumption of ovulation with rosiglitazone therapy has not been evaluated in clinical studies, and, therefore, is unknown. 1 If menstrual dysfunction occurs, weigh risks versus benefits of continued rosiglitazone.1

Hepatic Effects

No evidence of hepatotoxicity has been noted with rosiglitazone in clinical studies to date, including a long-term (4-6 years) study (ADOPT) in patients with recently diagnosed type 2 diabetes mellitus.1,30,104,109,126 In the ADOPT study, the incidence of ALT elevation exceeding 3 times the upper limit of normal was similar in patients receiving rosiglitazone or active comparators (i.e., glyburide or metformin).1,126 However, hepatitis, elevations in hepatic enzymes to at least 3 times the upper limit of normal, and liver failure with or without fatalities have been reported during postmarketing experience with rosiglitazone.1

Liver function tests are recommended in patients receiving rosiglitazone (prior to therapy, then periodically according to clinician judgment).1 Therapy with rosiglitazone should not be initiated if baseline ALT concentrations exceed 2.5 times the upper limit of normal.1 Patients with mildly elevated liver enzymes (e.g., ALT not exceeding 2.5 times the upper limit of normal) prior to or during therapy should be evaluated to determine the cause of the elevation; rosiglitazone should be initiated or continued in such patients with caution and close clinical monitoring.1

If ALT increases to more than 3 times the upper limit of normal at any time during therapy, liver function tests should be rechecked as soon as possible.1 Development of manifestations suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine) also should prompt rechecking of liver function.1 The decision whether to continue therapy should be guided by clinical judgment pending laboratory evaluation.1 If ALT increases to 3 times the upper limit of normal during therapy and remains elevated, or if jaundice develops, rosiglitazone should be discontinued.1

Hematologic Effects

Dose-related decreases in hemoglobin (not exceeding 1 g/dL) and hematocrit (not exceeding 3.3%) usually become evident within the first 3 months after initiation of therapy with rosiglitazone alone and in combination with other antidiabetic agents.1,30 Slight decreases in leukocyte counts have been observed in patients receiving rosiglitazone.1 These effects may be related to plasma volume expansion.1,30

Ocular Effects

During postmarketing experience, rare cases of new-onset or worsening (diabetic) macular edema with decreased visual acuity have been reported with rosiglitazone or another thiazolidinedione; such patients frequently reported concurrent peripheral edema.1,119,146 Some patients with macular edema presented with symptoms of blurred vision or decreased visual acuity, but other cases were detected by routine ophthalmologic examination.1 Symptoms improved in some patients following discontinuance of rosiglitazone or, rarely, after dosage reduction.1,119 Patients with diabetes mellitus should have regular eye examinations by an ophthalmologist.1,114 Patients receiving rosiglitazone who report any visual symptoms should be referred promptly to an ophthalmologist, regardless of the presence of other concurrent therapy or physical findings.1

Specific Populations

Pregnancy

Category C.1 The background risk of birth defects, pregnancy loss, or other adverse outcomes is increased in pregnancies complicated by hyperglycemia and may be decreased with good glycemic control.1 Most clinicians recommend use of insulin monotherapy for maintenance of optimum blood glucose concentrations during pregnancy.1 Women with diabetes mellitus or a history of gestational diabetes who are pregnant or planning pregnancy require excellent blood glucose control before conception and throughout pregnancy.1 Careful monitoring of blood glucose concentration is essential in such patients.1 Rosiglitazone should be used during pregnancy only when the potential benefits justify the possible risk to the fetus.1

Lactation

Rosiglitazone-related material is distributed into milk in rats; it is not known whether the drug is distributed into human milk.1,146 Because many drugs are distributed into human milk, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1,146

Pediatric Use

Rosiglitazone has been studied in children and adolescents 10-17 years of a data are insufficient to recommend use in pediatric patients younger than 18 years of age.1 The manufacturer states that safety and efficacy of rosiglitazone have not been established in pediatric patients.1 However, the American Diabetes Association (ADA) states that most pediatric diabetologists use oral antidiabetic agents in children with type 2 diabetes mellitus because of greater patient compliance with therapy and convenience for the patient's family and a lack of evidence demonstrating better efficacy of insulin as initial therapy for type 2 diabetes mellitus.107

Geriatric Use

Pharmacokinetic and adverse effect profiles of rosiglitazone similar to those in younger adults.1 Dosage adjustment based solely on age is not necessary in geriatric patients receiving rosiglitazone alone.1

Data from several observational studies suggest that the risk of all-cause mortality may be increased in geriatric diabetic patients 65 years of age or older receiving rosiglitazone versus another thiazolidinedione antidiabetic agent (pioglitazone).1

Hepatic Impairment

Rosiglitazone should be used with caution in patients with mild hepatic impairment; use is not recommended in moderate to severe hepatic impairment (ALT exceeding 2.5 times upper limit of normal, or active liver disease).1 (See Hepatic Effects under Warnings/Precautions: General Precautions, in Cautions.)

Common Adverse Effects

Adverse effects of rosiglitazone occurring in at least 2% of patients include upper respiratory tract infection,1,30 injury,1 headache,1,30 edema,1 back pain,1 hyperglycemia,1 fatigue,1 sinusitis,1 and diarrhea.1 Anemia and edema generally were mild to moderate and usually did not require discontinuance.1 Rosiglitazone-induced reductions in hyperglycemia are associated with mild weight gain.1 Increased total, low-density lipoprotein (LDL)-, and high-density lipoprotein (HDL)-cholesterol; LDL/HDL-cholesterol ratio generally decreases after initial increase.1

Adverse effects generally were similar with rosiglitazone monotherapy versus combined therapy with metformin; however, anemia was more common during combined therapy (7.1 versus 1.9%) with metformin compared with that in patients receiving rosiglitazone monotherapy or combination therapy with a sulfonylurea.1 Hypoglycemia occurs infrequently with rosiglitazone therapy.1,30 However, hypoglycemia was more common during combined therapy with rosiglitazone and metformin, a sulfonylurea, or insulin. In addition, self-monitored blood glucose measurements of 50 mg/dL or less were reported by 22% of patients receiving the fixed combination of glyburide and metformin hydrochloride plus rosiglitazone compared with 3.3% of patients receiving the fixed combination of glyburide and metformin hydrochloride.111 Hypoglycemia, confirmed by capillary blood glucose concentrations of 50 mg/dL or less, was reported by 12 or 14% of patients receiving combination therapy with insulin and rosiglitazone at dosages of 4 or 8 mg, respectively, compared with 6% of patients receiving insulin alone.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors (e.g., gemfibrozil) or inducers (e.g., rifampin) of cytochrome P-450 (CYP) isoenzyme 2C8; potential pharmacokinetic interaction.1,104 With concurrent gemfibrozil, potential pharmacokinetic interaction (increased area under the concentration-time curve [AUC] for rosiglitazone).1 With concurrent rifampin, potential pharmacokinetic interaction (decreased AUC for rosiglitazone).1 Adjustments in rosiglitazone dosage may be needed during initiation or discontinuance of an inhibitor or inducer of CYP2C8.1

Because rosiglitazone does not affect CYP3A4, pharmacokinetic interactions unlikely with drugs metabolized mainly via this isoenzyme (e.g., nifedipine, estrogen-progestin combination contraceptives).1,30

Antidiabetic Agents

Additive glycemic control with metformin; no pharmacokinetic interaction.1,30

Additive glycemic control with glimepiride; no pharmacokinetic interaction.1

Acarbose reduced extent of absorption and prolonged half-life, but not considered clinically important;1 effect of combined rosiglitazone and acarbose on glycemic control remains to be established.104

Although the manufacturer states that glyburide-induced reductions in blood glucose are unaltered by short-term (7 days) rosiglitazone in patients stabilized on the sulfonylurea,1 rosiglitazone can improve glycemic control during long-term combined therapy.30,104,105,106 With concurrent glyburide in Caucasian individuals, potential pharmacokinetic interaction (decreased glyburide concentrations).1 With concurrent glyburide in Japanese individuals, potential pharmacokinetic interaction (slightly increased glyburide concentrations).1

Increased risk of congestive heart failure (CHF) with concomitant insulin therapy.1,128 Concomitant use of rosiglitazone and insulin therapy is not recommended.1 (See Congestive Heart Failure under Warnings/Precautions: Warnings, in Cautions.)

Alcohol

Rosiglitazone-exacerbated hypoglycemia unlikely.1

Digoxin

Pharmacokinetic interaction unlikely.1,30

Ranitidine

Pharmacokinetic interaction unlikely.1

Warfarin

Pharmacokinetic interaction unlikely.1

Description

Rosiglitazone is a thiazolidinedione (glitazone) antidiabetic agent that is structurally and pharmacologically related to pioglitazone and troglitazone but unrelated to other antidiabetic agents, including sulfonylureas, biguanides, and α-glucosidase inhibitors.1,3,4,6,7,9,10,11,13,14,16,20,30

Rosiglitazone acts principally by increasing insulin sensitivity in target tissues, as well as decreasing hepatic gluconeogenesis.1,2,6,7,10,11,13,16,20,30 Rosiglitazone is a peroxisome proliferator-activated receptor_γ (PPAR_γ) agonist that increases transcription of insulin-responsive genes and increases insulin sensitivity.1,2,3,4,9,13,14,16,20,30 Rosiglitazone, like other thiazolidinediones, ameliorates insulin resistance associated with type 2 diabetes mellitus without stimulating insulin release from pancreatic β cells, thus avoiding the risk of hypoglycemia.1,7,10,13 Because rosiglitazone does not lower glucose concentrations below euglycemia,1,7 the drug is appropriately referred to as an antidiabetic agent rather than a hypoglycemic agent. Some evidence suggests that the glucoregulatory effects of thiazolidinediones are mediated in part via reduced systemic and tissue lipid availability.10,13,14,16,30 Circulating concentrations of insulin and C-peptide are reduced during rosiglitazone therapy.1,10 Rosiglitazone is extensively metabolized,1,30 principally via the cytochrome P-450 (CYP) 2C8 isoenzyme;1 unlike troglitazone, rosiglitazone does not induce CYP3A4-mediated metabolism.1,30 Because of the delayed onset of action of rosiglitazone (2 weeks) and other thiazolidinediones and potential adverse effects, therapy with the drugs should not be initiated in hospitalized patients with diabetes mellitus.114 (See Congestive Heart Failure under Warnings/Precautions: Warnings, in Cautions.)

Advice to Patients

Importance of patient reading medication guide before starting rosiglitazone and each time the prescription is refilled.146

Importance of informing patients of the current state of knowledge regarding the cardiovascular risks of rosiglitazone, and that although there is some evidence suggesting an increased risk of myocardial infarction compared with placebo, data from long-term clinical trials, including a cardiovascular outcomes trial, generally have not confirmed these findings.1 (See General Precautions: Major Adverse Cardiovascular Events, under Warnings/Precautions in Cautions.)

Importance of informing patients that rosiglitazone is not recommended for patients with symptomatic heart failure.1,146,149,150 Importance of identifying and reporting to clinicians potential symptoms of congestive heart failure (CHF), such as unusually rapid increase in weight, edema, unusual fatigue, or shortness of breath.1,128,146

Importance of patients not taking rosiglitazone if they are allergic to the drug or any ingredients in the tablet.1,146 Signs and symptoms of a severe allergic reaction to rosiglitazone include swelling of the face, lips, tongue, or throat; problems breathing or swallowing; rash, itching, or hives; blisters on the skin or in the mouth, nose, or eyes; skin peeling; faintness or dizziness; rapid heartbeat.1,146

Importance of taking exactly as prescribed.1 Importance of taking a missed dose as soon as possible, unless it is almost time for next dose.1,146 Do not double dose to make up for the missed dose.1,146 Importance of immediately contacting a clinician or a poison control center if accidental overdosage occurs.1,146

Importance of continuing rosiglitazone therapy even if response is not evident within 2 weeks; full therapeutic response may not be evident for 2-3 months after initiation of therapy.1,146

Risk of pregnancy in premenopausal anovulatory women with insulin resistance.1 Advise patients regarding use of effective contraception during therapy.1,146

Importance of diet and exercise regimen adherence.1,146 Importance of regular monitoring (preferably self-monitoring) of blood glucose and glycosylated hemoglobin (HbA_1c) concentrations.1,146

Importance of informing patients that rosiglitazone is not recommended in patients taking insulin due to potentially increased risk of CHF.1,146

Risk of hypoglycemia in patients receiving concomitant antidiabetic agent therapy.1 Provide instructions regarding management of hypoglycemia, including recognition of symptoms, predisposing conditions, and treatment.1

Importance of liver function test monitoring and immediate reporting of potential manifestations of hepatotoxicity (e.g., nausea or vomiting, abdominal pain, unusual fatigue, loss of appetite, dark urine, yellowing of skin or whites of eyes).1,146

Risk of fractures (e.g., hand, upper arm, foot) in women.1,145,146,147

Importance of regular eye examinations.1 Importance of reporting changes in vision to clinician.146

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., drugs that affect blood glucose concentrations; nitrates; antihypertensive agents; antilipemic agents; agents for CHF or prevention of coronary heart disease or stroke) and dietary or herbal supplements,146 as well as any concomitant illnesses (e.g., CHF or other cardiac disease, type 1 diabetes mellitus, history of diabetic ketoacidosis, macular edema, liver disease, history of liver disease associated with troglitazone, irregular menstrual periods).1,146

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1,146

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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