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Rosiglitazone (Monograph)

Brand name: Avandia
Drug class: Thiazolidinediones
VA class: HS502
Chemical name: (±)-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]-phenyl]methyl]-2,4-thiazolidinedione, (Z)-2-butenedioate
Molecular formula: C18H19N3O3S•C4H4O4
CAS number: 122320-73-4

Medically reviewed by Drugs.com on Jun 11, 2024. Written by ASHP.

Warning

    Congestive Heart Failure

  • Thiazolidinediones, including rosiglitazone, cause or exacerbate CHF in some patients.1 116 117 128 141 143 Monitor patients for signs and symptoms of CHF (e.g., excessive, rapid weight gain; dyspnea; and/or edema) after initiation of therapy and dosage titration.1 117 128 If CHF signs and symptoms develop, manage according to current standards of care; in addition, consider discontinuance or reduction in dosage of rosiglitazone.1 117 128

  • Not recommended in patients with symptomatic heart failure.1 113

  • Initiation of rosiglitazone in patients with NYHA class III or IV heart failure contraindicated.1 128 (See Congestive Heart Failure under Cautions.)

Introduction

Antidiabetic agent; thiazolidinedione (glitazone).1 2 3 4 6 7 9 10 11 13 14 16 20 30

Uses for Rosiglitazone

Type 2 Diabetes Mellitus

Used as monotherapy or in combination with a sulfonylurea, metformin, or a sulfonylurea and metformin as an adjunct to diet and exercise for the management of type 2 diabetes mellitus.1 30 106 111 112 121 122

May be added to glyburide/metformin fixed-combination therapy if hyperglycemia is not adequately controlled with the fixed combination.111

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 A1c; HbA1c], weight, and cardiovascular mortality).698 704 705

In patients with metformin contraindications or intolerance (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

May need to initiate therapy with 2 agents (e.g., metformin plus another drug) in patients with high initial HbA1c (>7.5% or ≥1.5% above target).698 704 In such patients with metformin intolerance, some experts suggest initiation of therapy with 2 drugs from other antidiabetic drug classes with complementary mechanisms of action.698 704

Consider early initiation of combination therapy for the treatment of type 2 diabetes mellitus to extend the time to treatment failure and more rapidly attain glycemic goals.704

For patients with inadequate glycemic control on metformin monotherapy, consider 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 preferences when selecting additional antidiabetic agents for combination therapy.698 699 704 705 706

Consider early introduction of insulin for severe hyperglycemia (e.g., blood glucose of ≥300 mg/dL or HbA1c >9–10%), especially if accompanied by catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698 704 However, use of rosiglitazone in combination with insulin not recommended.1 (See Congestive Heart Failure under Cautions and also see Specific Drugs under Interactions.)

Manufacturer states that rosiglitazone should not be used for type 1 diabetes mellitus or treatment of diabetic ketoacidosis.1 146

Rosiglitazone Dosage and Administration

General

Administration

Oral Administration

Administer rosiglitazone once or twice daily without regard to meals.1 25 146

If a dose is missed, take the missed dose as soon as it is remembered.1 146 If the missed dose is remembered at the time of the next dose, skip missed dose and resume the regular schedule.1 146 Do not double dose to replace missed dose.1 146

Dosage

Available as rosiglitazone maleate; dosage expressed in terms of rosiglitazone.1

Adults

Type 2 Diabetes Mellitus
Monotherapy
Oral

Usual initial dosage is 4 mg daily in 1 or 2 divided doses.1 146 If response is inadequate after 8–12 weeks, may increase dosage to a maximum of 8 mg daily.1

Prescribing Limits

Adults

Type 2 Diabetes Mellitus
Oral

Maximum 8 mg daily.1

Special Populations

Hepatic Impairment

Do not initiate therapy in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).1

Renal Impairment

No dosage adjustment necessary.1

Geriatric Patients

No dosage adjustment necessary.1

Detailed Rosiglitazone dosage information

Cautions for Rosiglitazone

Contraindications

Warnings/Precautions

Warnings

Congestive Heart Failure

Risk of fluid retention; may cause or exacerbate CHF.1 116 117 128 141 143 Use of thiazolidinediones associated with approximately twofold increased risk of CHF.131 143 148 151 155 (See Boxed Warning and also see Edema under Cautions.)

Use with caution in patients with edema and in those who are at risk for CHF.1 117 148 Initiation of rosiglitazone not recommended in patients experiencing an acute coronary event.1 If an acute coronary event occurs, consider discontinuance of rosiglitazone during the acute phase.1 Use not recommended in patients with NYHA class III or IV cardiac status or those with symptomatic heart failure.1 113 149 150 Thiazolidinedione therapy should not be initiated in hospitalized patients with diabetes mellitus because of delayed onset of action and potential for increased vascular volume and CHF.114

Increased incidence of adverse cardiovascular events (e.g., edema, need for additional CHF therapy) reported in patients with NYHA class I or II heart failure receiving rosiglitazone in addition to other antidiabetic and CHF therapy.1 128 142 No change in left ventricular ejection fraction observed.1 128 142

Increased risk of CHF observed in patients receiving rosiglitazone and insulin compared with those receiving insulin alone.1 128 (See Specific Drugs under Interactions.)

General Precautions

Major Adverse Cardiovascular Events

Findings from several meta-analyses of principally short-term trials and observational studies suggested a possible association between rosiglitazone and an increased risk of MI.1 128 130 132 144 148 151 155 217 220 However, these findings have not been confirmed in long-term (>3 years), prospective randomized studies.1 220 These studies, which include a cardiovascular outcomes trial (RECORD), generally have found no evidence of an increased risk of mortality or major adverse cardiovascular effects (MACE) with rosiglitazone compared with metformin and/or a sulfonylurea.1

Although some uncertainty remains regarding the cardiovascular risk of rosiglitazone, FDA states that concerns have been substantially reduced based on current evidence.220 223

Edema

Fluid retention reported; may lead to or exacerbate CHF.1 116 117 128 Weight gain reported; may involve fluid retention and fat accumulation.1 117

Use with caution in patients with edema and in those at risk for CHF.1 117 148 Monitor for weight gain and edema.1 117 Evaluate any patient developing edema within first few months of therapy for possible CHF.117 (See Congestive Heart Failure under Cautions.)

Musculoskeletal Effects

Risk of bone loss and fractures in women, and possibly men.1 125 126 127 139 145 147 151 Fractures reported more frequently in women receiving long-term therapy (4–6 years) with rosiglitazone (9.3%) than in women receiving metformin (5.1%) or glyburide (3.5%).1 125 126 147 Effects noted after first year of treatment and persisted throughout treatment.1 Majority of fractures were in upper limb (upper arm, hand, wrist) or distal lower limb (foot, ankle, fibula, tibia).1 125 127 147 Although increased risk of fracture may also apply to men, risk appears higher among women than men.1

Consider risk of fracture.1 125 127 147 Assess and maintain bone health according to current standards of care.1 125 147

Hematologic Effects

Possible dose-related decreases in hemoglobin (≤1 g/dL) and hematocrit (≤3.3%); usually evident within 3 months after initiation of therapy or dosage increase.1 30 Possible modest decreases in leukocyte counts.1 Hematologic effects may be related to plasma volume expansion.1 30

Ocular Effects

New-onset or worsening (diabetic) macular edema with decreased visual acuity reported; some patients reported concurrent peripheral edema.1 119 Some patients were symptomatic (e.g., blurred vision, decreased visual acuity); other cases were detected by routine ophthalmologic examination.1 Symptoms improved in some patients after discontinuance or rarely after dosage reduction.1 119

Regular eye examinations by an ophthalmologist recommended in patients with diabetes mellitus.1 114 Patients with any visual symptoms should be promptly evaluated by an ophthalmologist.1

Ovulatory Effects

Possible ovulation in premenopausal anovulatory women; risk of pregnancy unless contraceptive measures initiated.1 If unexpected menstrual dysfunction occurs, weigh risks versus benefits of continued therapy.1

Hepatic Effects

No evidence of hepatotoxicity in clinical studies to date.1 30 104 109 126 However, hepatitis, elevations in hepatic enzymes, and hepatic failure associated with fatalities reported during postmarketing experience.1

Monitor liver function tests prior to initiation of therapy and periodically thereafter according to clinician judgment.1 Do not initiate therapy if baseline ALT concentrations >2.5 times ULN.1 Evaluate patients with mildly elevated liver enzymes (e.g., ALT ≤2.5 ULN) prior to or during therapy to determine cause; initiate or continue drug with caution and close clinical monitoring.1 (See Hepatic Impairment under Cautions.)

Recheck liver enzymes as soon as possible if ALT increases to >3 times the ULN.1 Discontinue therapy if ALT remains elevated at >3 times ULN.1 Check liver function if manifestations suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine) occur.1 Decision to continue therapy pending results of laboratory tests should be guided by clinician judgment.1 Discontinue if jaundice develops.1

Specific Populations

Pregnancy

Category C.1 Risk of birth defects, pregnancy loss, or other adverse outcomes increases in pregnancies complicated by hyperglycemia and may decrease with good glycemic control.1 Use during pregnancy only when potential benefits justify possible risk to the fetus.1 Most clinicians recommend use of insulin during pregnancy to maintain optimum control of blood glucose concentrations.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 146 Discontinue nursing or the drug.1 146

Pediatric Use

Has been evaluated in children and adolescents 10–17 years of age.1 Manufacturer states that data are insufficient to recommend use in pediatric patients <18 years of age.1

ADA states that use of oral antidiabetic agents may be considered in children with type 2 diabetes mellitus because of the greater compliance and convenience and lack of evidence demonstrating better efficacy of insulin for type 2 diabetes mellitus.107

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution in patients with mild hepatic impairment (ALT ≤2.5 times the ULN).1 Use not recommended in patients with ALT >2.5 times ULN.1 (See Hepatic Effects under Cautions.)

Common Adverse Effects

Upper respiratory tract infection,1 30 injury,1 headache.1

Drug Interactions

Metabolized principally by CYP2C8 and, to a lesser extent, by CYP2C9.1 Does not inhibit CYP isoenzymes.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP2C8: Potential pharmacokinetic interaction.104 Changes in antidiabetic therapy may be necessary when these drugs are initiated or discontinued during rosiglitazone therapy.1

Drugs metabolized by CYP3A4: Pharmacokinetic interaction unlikely.1 30

Specific Drugs

Drug

Interaction

Comments

Acarbose

Clinically important pharmacokinetic interaction unlikely1

Alcohol

Pharmacologic interaction (i.e., increased risk of hypoglycemia) unlikely1

Antidiabetic agents (See entries for acarbose, glimepiride, glyburide, and metformin)

Possible hypoglycemia1

May need to reduce dosage of concomitant antidiabetic agents1

Digoxin

Pharmacokinetic interaction unlikely1 30

Gemfibrozil

Potential increased AUC of rosiglitazone1

May need to reduce rosiglitazone dosage when gemfibrozil therapy is initiated1

Glimepiride

Additive glycemic control1

Pharmacokinetic interaction unlikely1

Glyburide

Variable effects on peak plasma concentrations and AUC of glyburide, depending on race1

Enhanced glycemic control following long-term combined therapy30 104 105 106

Insulin

Increased risk of CHF128

Concomitant use not recommended1

Metformin

Pharmacokinetic interaction unlikely1

Additive glycemic control1 30

Nifedipine

Pharmacokinetic interaction unlikely1

Oral contraceptives, hormonal (ethinyl estradiol, norethindrone)

Pharmacokinetic interaction unlikely1

Ranitidine

Pharmacokinetic interaction unlikely1

Rifampin

Potential decreased rosiglitazone AUC1

May need to adjust dosage of rosiglitazone during initiation or discontinuance of rifampin1

Warfarin

Pharmacokinetic interaction unlikely1
Rosiglitazone drug interactions (more detail)

Rosiglitazone Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained about 1 hour after dosing.1

Absolute bioavailability is 99%.1 219

Onset

A therapeutic response usually is apparent within 2 weeks.1 Maximum response occurs within 2–3 months.1

Food

Food decreases peak plasma concentration and delays time to peak concentration; not clinically relevant.1 (See Administration under Dosage and Administration.)

Distribution

Extent

Distributed into milk in rats.1 Not known whether the drug distributes into human milk.1 Crosses human placenta and is detectable in fetal tissues.1 Clinical importance unknown.1

Plasma Protein Binding

Approximately 99.8% (mainly albumin).1

Elimination

Metabolism

Extensively metabolized, principally by CYP2C81 and, to a lesser extent, by CYP2C9.1

Elimination Route

Excreted primarily in urine (64%) and in feces (23%) as metabolites.1

Half-life

Approximately 3–4 hours.1 219

Special Populations

In patients with hepatic disease, elimination half-life is prolonged by about 2 hours.1 In patients with moderate to severe hepatic impairment (Child-Pugh class B or C), clearance of unbound drug decreased.1

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).1

Actions

Advice to Patients

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Rosiglitazone Maleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2 mg (of rosiglitazone)

Avandia

GlaxoSmithKline

4 mg (of rosiglitazone)

Avandia

GlaxoSmithKline

8 mg (of rosiglitazone)

Avandia

GlaxoSmithKline

AHFS DI Essentials™. © Copyright 2024, Selected Revisions June 21, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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