Rosiglitazone

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Avandia: 2 mg, 4 mg

Pharmacology

Mechanism of Action

Thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion. It has a mechanism of action that is dependent on the presence of insulin for activity. Rosiglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). Activation of nuclear PPARgamma receptors influences the production of a number of gene products involved in glucose and lipid metabolism. PPARgamma is abundant in the cells within the renal collecting tubules; fluid retention results from stimulation by thiazolidinediones which increases sodium reabsorption.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss (apparent): 17.6 L

Metabolism

Hepatic (99%) via CYP2C8; minor metabolism via CYP2C9

Excretion

Urine (~64%) and feces (~23%) as metabolites

Onset of Action

Delayed; Maximum effect: Up to 12 weeks

Time to Peak

1 hour; delayed with food

Half-Life Elimination

3 to 4 hours; prolonged by approximately 2 hours in patients with moderate-to-severe hepatic impairment

Protein Binding

99.8%; primarily albumin

Use in Specific Populations

Special Populations: Hepatic Function Impairment

In moderate to severe liver disease (Child-Pugh class B or C), unbound oral Cl was significantly lower, C_max and AUC were increased 2- and 3-fold, respectively.

Special Populations: Gender

Mean oral Cl in women was approximately 6% lower.

Special Populations Note

Body weight: Cl and steady-state V_d increase with increased body weight.

Use: Labeled Indications

Diabetes mellitus, type 2: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Contraindications

US labeling: Hypersensitivity to rosiglitazone or any component of the formulation; NYHA Class III/IV heart failure (initiation of therapy)

Canadian labeling: Hypersensitivity to rosiglitazone or any component of the formulation; any stage of heart failure (eg, NYHA Class I, II, III, IV); serious hepatic impairment; pregnancy

Dosage and Administration

Dosing: Adult

Diabetes mellitus, type 2 Oral:

Initial: 4 mg/day as a single dose or in 2 divided doses If response is inadequate after 8 to 12 weeks of treatment, the dosage may be increased to 8 mg/day as a single dose or in 2 divided doses daily; maximum dose: 8 mg/day. Per some clinical trial data, 4 mg twice daily may lower fasting plasma glucose and HbA_1c more effectively than 8 mg once daily

Note: When used in combination therapy with other hypoglycemic agents, a dose reduction of the concurrent agent may be necessary if hypoglycemia occurs.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Type 2 diabetes: Children ≥10 years and Adolescents: Limited data available: Oral: Initial: 2 mg twice daily; then increase to 4 mg twice daily after 8 weeks; in combination with metformin; dosing presented was used 233 pediatric patients as part of a larger multicenter comparative trial of treatments (n=699) and results showed rosiglitazone and metformin more effective than other treatment arms (ie, metformin alone or metformin and lifestyle changes) at maintaining glycemic control (Copeland, 2011; The TODAY Study Group, 2007; The TODAY Study Group, 2012).

Administration

Oral: May be administered without regard to meals.

Dietary Considerations

Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM) should include diet control.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from light.

Drug Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Atazanavir: May increase the serum concentration of Rosiglitazone. Monitor therapy

Cholestyramine Resin: May decrease the serum concentration of Rosiglitazone. Management: Administer rosiglitazone at least 2 hours prior to cholestyramine in order to minimize the likelihood of an interaction, and monitor patients closely for evidence of reduced rosiglitazone effectiveness. Consider therapy modification

CYP2C8 Inducers (Moderate): May decrease the serum concentration of Rosiglitazone. Monitor therapy

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Rosiglitazone. Monitor therapy

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulins: May enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Avoid combination

Letermovir: May increase the serum concentration of Rosiglitazone. Monitor therapy

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Monitor therapy

Maitake: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pregabalin: May enhance the fluid-retaining effect of Thiazolidinediones. Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sulfonylureas: Thiazolidinediones may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Vasodilators (Organic Nitrates): May enhance the adverse/toxic effect of Rosiglitazone. Specifically, a greater risk of ischemia and other adverse effects has been associated with this combination in some pooled analyses. Monitor therapy

Adverse Reactions

Note: As reported in monotherapy studies; the rate of certain adverse reactions (eg, anemia, edema, hypoglycemia) may be higher with some combination therapies. Rare cases of hepatocellular injury have been reported in men in their 60s within 2 to 3 weeks after initiation of rosiglitazone therapy. LFTs in these patients revealed severe hepatocellular injury which responded with rapid improvement of liver function and resolution of symptoms upon discontinuation of rosiglitazone. Patients were also receiving other potentially hepatotoxic medications (Al-Salman 2000; Freid 2000).

>10%: Endocrine & metabolic: Increased HDL cholesterol, increased LDL cholesterol, increased serum cholesterol (total), weight gain

1% to 10%:

Cardiovascular: Edema (5%), hypertension (4%); cardiac failure (≤3% in patients receiving insulin; incidence likely higher in patients with pre-existing cardiac failure), ischemic heart disease (3%; incidence likely higher in patients with pre-existing CAD)

Central nervous system: Headache (6%)

Endocrine & metabolic: Hypoglycemia (1% to 3%; combination therapy with insulin: 12% to 14%)

Gastrointestinal: Diarrhea (3%)

Hematologic & oncologic: Anemia (2%)

Neuromuscular & skeletal: Bone fracture (≤9%; incidence greater in females; usually upper arm, hand, or foot), arthralgia (5%), back pain (4% to 5%)

Respiratory: Upper respiratory tract infection (4% to 10%), nasopharyngitis (6%)

Miscellaneous: Trauma (8%)

<1%, postmarketing, and/or case reports: Anaphylaxis, angina pectoris, angioedema, blurred vision, cardiac arrest, coronary artery disease, coronary thrombosis, decreased HDL cholesterol, decreased hematocrit, decreased hemoglobin, decreased visual acuity, decreased white blood cell count, dyspnea, hepatic failure, hepatitis, increased serum bilirubin, increased serum transaminases, jaundice (reversible), macular edema, myocardial infarction, pleural effusion, pruritus, pulmonary edema, skin rash, Stevens-Johnson syndrome, thrombocytopenia, urticaria, weight gain (rapid, excessive; usually due to fluid accumulation)

Warnings/Precautions

Concerns related to adverse effects:

• Edema: Dose-related edema may occur. Use with caution in patients with edema; may increase plasma volume and/or cause fluid retention. Monitor for signs/symptoms of heart failure.
• Fractures: Increased incidence of bone fractures in females treated with rosiglitazone was observed during analysis of long-term trial; majority of fractures occurred in the upper arm, hand and foot (differing from the hip or spine fractures usually associated with postmenopausal osteoporosis). Consider risk of fracture prior to initiation and during use.
• Heart failure/cardiac effects: [US Boxed Warning]: Thiazolidinediones, including rosiglitazone, may cause or exacerbate congestive heart failure; closely monitor for signs and symptoms of congestive heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases. If heart failure develops, treat accordingly and consider dose reduction or discontinuation. Not recommended for use in any patient with symptomatic heart failure. Initiation of therapy is contraindicated in patients with NYHA class III or IV heart failure. A higher frequency of cardiovascular events has been noted in patients with NYHA class I or II heart failure treated with rosiglitazone. Use may also be associated with an increased risk of angina and MI. Use with caution in patients at risk for cardiovascular events and monitor closely. Discontinue if any deterioration in cardiac status occurs.
• Hematologic effects: May decrease hemoglobin, hematocrit, and/or WBC count (slight); effects may be related to increased plasma volume and/or dose-related. Changes in hemoglobin and hematocrit generally occurred during the first 3 months after initiation of therapy and after dose increases. Use with caution in patients with anemia.
• Hypoglycemia: The risk of hypoglycemia is increased when rosiglitazone is combined with other hypoglycemic agents; dosage adjustment of concomitant hypoglycemic agents may be necessary.
• Macular edema: Has been reported with thiazolidinedione use, including rosiglitazone; some patients with macular edema presented with blurred vision or decreased visual acuity, and most had peripheral edema at time of diagnosis. In addition to regular ophthalmic exams, diabetic patients with visual symptoms should receive prompt ophthalmic evaluation. Improvement in macular edema may occur with discontinuation of therapy.
• Weight gain: Dose-related weight gain observed with use; mechanism unknown but likely associated with fluid retention and fat accumulation.

Disease-related concerns:

• Bariatric surgery:

– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2013; Melissas 2013).

– Weight gain: Evaluate risk vs benefit and consider alternative therapy after gastric bypass, sleeve gastrectomy, and gastric banding; weight gain may occur (Apovian 2015).

• Hepatic impairment: Use with caution in patients with elevated transaminases (AST or ALT); do not initiate in patients with active liver disease or ALT >2.5 times the upper limit of normal (ULN) at baseline; evaluate patients with ALT ≤2.5 times ULN at baseline or during therapy for cause of enzyme elevation; during therapy, if ALT >3 times ULN, reevaluate levels promptly and discontinue if elevation persists or if jaundice occurs at any time during use. Idiosyncratic hepatotoxicity has been reported with another thiazolidinedione agent (troglitazone); avoid use in patients who previously experienced jaundice during troglitazone therapy.
• Ischemic heart disease: Do not initiate in patients with stable ischemic heart disease due to an increased risk of cardiovascular complications (Fihn 2012).
• Stress-related states: It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Not indicated for use in patients with type 1 diabetes mellitus or with diabetic ketoacidosis (DKA).
• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Monitoring Parameters

Hemoglobin A_1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2019]), fasting blood glucose

Liver enzymes (prior to initiation of therapy, then periodically thereafter); evaluate patients with ALT ≤2.5 times ULN at baseline or during therapy for cause of enzyme elevation. Patients with an elevation in ALT >3 times ULN during therapy should be rechecked as soon as possible. If the ALT levels remain >3 times ULN, therapy with rosiglitazone should be discontinued.

Signs and symptoms of fluid retention or heart failure (periodically and with dose adjustments); weight gain (periodically and with dose adjustments); ophthalmic exams (at least every one to two years, or more frequently if symptoms dictate) (ADA 2019); fractures/fracture risk

Pregnancy

Pregnancy Considerations

Rosiglitazone crosses the placenta (Chan 2005).

Inadvertent use early in pregnancy has been reported, although in the majority of cases, the medication was stopped as soon as pregnancy was detected (Chan 2005; Kalyoncu 2005; Yaris 2004).

Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA_1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2020; Blumer 2013).

Agents other than rosiglitazone are currently recommended to treat diabetes mellitus in pregnancy (ADA 2020).

Thiazolidinediones may cause ovulation in anovulatory premenopausal females, increasing the risk of unintended pregnancy. Due to long-term safety concerns associated with their use, thiazolidinediones should be avoided in females of reproductive age (Fauser 2012).

Patient Education

What is this drug used for?

• It is used to lower blood sugar in patients with high blood sugar (diabetes).

Frequently reported side effects of this drug

• Headache
• Common cold symptoms
• Back pain
• Joint pain
• Stuffy nose
• Sore throat

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Severe cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes
• Bone pain
• Vision changes
• Severe loss of strength and energy
• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating
• Heart attack like chest pain; pain in arms, back, neck, jaw, or abdomen; shortness of breath; cold sweats; severe dizziness; passing out; or severe nausea or vomiting
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.