(roh si GLI ta zone)
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Avandia: 2 mg, 4 mg, 8 mg [DSC]
Brand Names: U.S.
- Antidiabetic Agent, Thiazolidinedione
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.
Vdss (apparent): 17.6 L
Hepatic (99%) via CYP2C8; minor metabolism via CYP2C9
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
3 to 4 hours; prolonged by approximately 2 hours in patients with moderate-to-severe hepatic impairment
99.8%; primarily albumin
Special Populations: Hepatic Function Impairment
In moderate to severe liver disease (Child-Pugh class B or C), unbound oral Cl was significantly lower, Cmax 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 Vd increase with increased body weight.
Use: Labeled Indications
Type 2 diabetes: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (noninsulin dependent, NIDDM); may be used as monotherapy or in combination with metformin or a sulfonylurea.
Limitations of use: Should not be used in patients with type 1 diabetes mellitus or diabetic ketoacidosis; use with insulin is not recommended.
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
Type 2 diabetes: Oral: Note: All patients should be initiated at the lowest recommended dose.
Initial: 4 mg daily as a single daily dose or in divided doses twice daily. If response is inadequate after 8-12 weeks of treatment, the dosage may be increased to 8 mg daily (maximum dose) as a single daily dose or in divided doses twice daily. In clinical trials, the 4 mg twice-daily regimen resulted in the greatest reduction in fasting plasma glucose and HbA1c.
Note: When used in combination therapy with other hypoglycemic agents, a dose reduction of the concurrent agent may be necessary if hypoglycemia occurs.
Refer to adult dosing.
Dosing: Renal Impairment
No dosage adjustment necessary.
Dosing: Hepatic Impairment
There are no dosage adjustments provided in the manufacturer’s labeling. Clearance is significantly lower in hepatic impairment; therapy should not be initiated if the patient exhibits active liver disease or increased transaminases (ALT >2.5 times the upper limit of normal) at baseline.
May be administered without regard to meals.
Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM) should include diet control.
Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from light.
Abiraterone Acetate: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy
Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination
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 (Strong): May increase the metabolism of CYP2C8 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates. Monitor therapy
CYP2C8 Inhibitors (Strong): May decrease the metabolism of CYP2C8 Substrates. Consider therapy modification
CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP2C8 Substrates. Management: Seek alternatives to the CYP2C8 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Deferasirox: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy
Gemfibrozil: May decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). Management: Limit pioglitazone maximum adult dose to 15 mg/day, and consider dose reduction of rosiglitazone, when used in combination with gemfibrozil. Consider therapy modification
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
Insulin: 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
Lumacaftor: May increase the serum concentration of CYP2C8 Substrates. Lumacaftor may decrease the serum concentration of CYP2C8 Substrates. Monitor therapy
MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
MiFEPRIStone: May increase the serum concentration of CYP2C8 Substrates. Management: Use CYP2C8 substrates at the lowest recommended dose, and monitor closely for adverse effects (including myopathy), during and in the 2 weeks following mifepristone treatment. Consider therapy modification
Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Pregabalin: May enhance the fluid-retaining effect of Antidiabetic Agents (Thiazolidinedione). Monitor therapy
Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics 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
RifAMPin: May increase the metabolism of Antidiabetic Agents (Thiazolidinedione). Management: Consider alternatives to the concomitant use of rifampin with thiazolidinedione antidiabetic agents. Monitor patients receiving these combinations for decreased effects of the thiazolidinedione derivative. Consider therapy modification
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: Antidiabetic Agents (Thiazolidinedione) 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
Trimethoprim: May decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). 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
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% (Limited to important or life-threatening): Anaphylaxis, angina pectoris, angioedema, 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, pulmonary edema, Stevens-Johnson syndrome, thrombocytopenia, weight gain (rapid, excessive; usually due to fluid accumulation)
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. According to the American Diabetes Association guidelines, thiazolidinediones should be avoided in patients with fracture risk factors (ADA 2016a).
• 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. Monitor blood glucose and HbA1c as clinically 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.
• Diabetes, type 1: Mechanism requires the presence of endogenous insulin; therefore, use in type 1 diabetes (insulin dependent, IDDM) or diabetic ketoacidosis is not recommended. Use with insulin is not recommended; may increase the risk of heart failure.
• 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.
• Premenopausal/anovulatory females: Use with caution in premenopausal, anovulatory women; may result in a resumption of ovulation, increasing the risk of pregnancy. Use of adequate contraception in premenopausal women is recommended.
Hemoglobin A1c (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 2016b]), fasting serum glucose; signs and symptoms of fluid retention or heart failure; ophthalmic exams.
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.
Pregnancy Risk Factor
Adverse effects were observed in initial animal reproduction studies. Rosiglitazone has been found to cross the placenta during the first trimester of pregnancy. Inadvertent use early in pregnancy has not been shown to increase the risk of adverse fetal effects, although in the majority of cases, the medication was stopped as soon as pregnancy was detected (Chan 2005; Kalyoncu 2005; Yaris 2004).
Thiazolidinediones may cause ovulation in anovulatory premenopausal women, increasing the risk of pregnancy. Adequate contraception in premenopausal women is recommended.
In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2016d; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2016d; Blumer 2013; Kitzmiller 2008).
Agents other than rosiglitazone are currently recommended to treat diabetes in pregnant women (ACOG 2013; Blumer 2013).
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience headache, common cold symptoms, joint pain, rhinitis, or pharyngitis. Have patient report immediately to prescriber signs of heart problems (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), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), bone pain, vision changes, severe loss of strength and energy, difficulty swallowing, tachycardia, signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating), or signs of a heart attack (angina; pain in arms, back, neck, jaw, or abdomen; shortness of breath; cold sweats; severe dizziness; passing out; or severe nausea or vomiting) (HCAHPS).
• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
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Other brands: Avandia