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.

Introduction

Antidiabetic agent; thiazolidinedione (glitazone).

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.

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

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).

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.

May need to initiate therapy with 2 agents (e.g., metformin plus another drug) in patients with high initial HbA_1c (>7.5% or ≥1.5% above target). 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.

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.

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.

Consider early introduction of insulin for severe hyperglycemia (e.g., blood glucose of ≥300 mg/dL or HbA_1c >9–10%), especially if accompanied by catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia. However, use of rosiglitazone in combination with insulin not recommended. (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.

Rosiglitazone Dosage and Administration

General

• Monitor regularly (e.g., fasting blood glucose concentrations, HbA_1c) to determine therapeutic response.

• Carefully monitor for fluid retention after dosage increases.

• Allow sufficient time to assess therapeutic response (8–12 weeks) to rosiglitazone.

Administration

Oral Administration

Administer rosiglitazone once or twice daily without regard to meals.

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

Dosage

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

Adults

Type 2 Diabetes Mellitus

Monotherapy

Oral

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

Prescribing Limits

Adults

Type 2 Diabetes Mellitus

Oral

Maximum 8 mg daily.

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).

Renal Impairment

No dosage adjustment necessary.

Geriatric Patients

No dosage adjustment necessary.

Cautions for Rosiglitazone

Contraindications

• Initiation of therapy in patients with NYHA class III or IV CHF. (See Boxed Warning.)

• History of hypersensitivity to the drug or any ingredient in the formulation.

Warnings/Precautions

Warnings

Congestive Heart Failure

Risk of fluid retention; may cause or exacerbate CHF. Use of thiazolidinediones associated with approximately twofold increased risk of CHF. (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. Initiation of rosiglitazone not recommended in patients experiencing an acute coronary event. If an acute coronary event occurs, consider discontinuance of rosiglitazone during the acute phase. Use not recommended in patients with NYHA class III or IV cardiac status or those with symptomatic heart failure. 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.

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. No change in left ventricular ejection fraction observed.

Increased risk of CHF observed in patients receiving rosiglitazone and insulin compared with those receiving insulin alone. (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. However, these findings have not been confirmed in long-term (>3 years), prospective randomized studies. 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.

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

Edema

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

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

Musculoskeletal Effects

Risk of bone loss and fractures in women, and possibly men. 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%). Effects noted after first year of treatment and persisted throughout treatment. Majority of fractures were in upper limb (upper arm, hand, wrist) or distal lower limb (foot, ankle, fibula, tibia). Although increased risk of fracture may also apply to men, risk appears higher among women than men.

Consider risk of fracture. Assess and maintain bone health according to current standards of care.

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. Possible modest decreases in leukocyte counts. Hematologic effects may be related to plasma volume expansion.

Ocular Effects

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

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

Ovulatory Effects

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

Hepatic Effects

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

Monitor liver function tests prior to initiation of therapy and periodically thereafter according to clinician judgment. Do not initiate therapy if baseline ALT concentrations >2.5 times ULN. 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. (See Hepatic Impairment under Cautions.)

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

Specific Populations

Pregnancy

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

Lactation

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

Pediatric Use

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

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.

Geriatric Use

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

Hepatic Impairment

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

Common Adverse Effects

Upper respiratory tract infection, injury, headache.

Drug Interactions

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

Drugs Affecting Hepatic Microsomal Enzymes

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

Drugs metabolized by CYP3A4: Pharmacokinetic interaction unlikely.

Specific Drugs

Rosiglitazone Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained about 1 hour after dosing.

Absolute bioavailability is 99%.

Onset

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

Food

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

Distribution

Extent

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

Plasma Protein Binding

Approximately 99.8% (mainly albumin).

Elimination

Metabolism

Extensively metabolized, principally by CYP2C8 and, to a lesser extent, by CYP2C9.

Elimination Route

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

Half-life

Approximately 3–4 hours.

Special Populations

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

Stability

Storage

Oral

Tablets

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

Actions

• Structurally and pharmacologically related to pioglitazone and troglitazone (no longer commercially available in the US); unrelated to other antidiabetic agents (e.g., sulfonylureas, biguanides, α-glucosidase inhibitors).

• A peroxisome proliferator-activated receptor_γ (PPAR_γ) agonist; increases transcription of insulin-responsive genes.

• Increases insulin sensitivity in target tissues and decreases hepatic gluconeogenesis. Ameliorates insulin resistance associated with type 2 diabetes mellitus without increasing insulin secretion from pancreatic β cells. Does not lower glucose concentrations below euglycemia. Reduces circulating concentrations of insulin and C-peptide.

• Ineffective in absence of endogenous insulin.

Advice to Patients

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

• Importance of informing patients of the current state of knowledge regarding the cardiovascular risk of rosiglitazone, and that although there is some evidence suggesting an increased risk of MI compared with placebo, data from long-term clinical trials, including a cardiovascular outcomes trial, generally have not confirmed these findings.

• Importance of informing patients that rosiglitazone is not recommended for patients with symptomatic heart failure. Importance of identifying and reporting to a clinician potential symptoms of CHF (e.g., unusually rapid increase in weight, edema, unusual fatigue, shortness of breath).

• Importance of patients not taking rosiglitazone if they are allergic to the drug or any ingredients in the tablet. Signs and symptoms of severe allergic reaction 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.

• Importance of taking exactly as prescribed. Importance of immediately contacting a clinician or a poison control center if accidental overdosage occurs.

• Importance of taking a missed dose as soon as possible, unless it is almost time for next dose. Do not double dose to make up for the missed dose.

• Importance of diet and exercise regimen adherence. Importance of regular monitoring of blood glucose and HbA_1c.

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

• Importance of continuing rosiglitazone therapy even if response is not evident in ≤2 weeks; full therapeutic response may not be evident for 2–3 months after initiation of therapy.

• Importance of regular eye examinations. Importance of reporting change in vision.

• 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).

• Risk of fractures (e.g., hand, upper arm, foot) in women.

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

• Risk of pregnancy in premenopausal anovulatory women. Advise patients regarding use of effective contraception during therapy.

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

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

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

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.

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