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Rosiglitazone

Pronunciation

(roh si GLI ta zone)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Avandia: 2 mg, 4 mg, 8 mg [DSC]

Brand Names: U.S.

  • Avandia

Pharmacologic Category

  • Antidiabetic Agent, Thiazolidinedione

Pharmacology

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.

Distribution

Vdss (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

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.

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

Dosing: Adult

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. The Canadian labeling recommends a maximum rosiglitazone dose of 4 mg daily when used in combination with a sulfonylurea.

Dosing: Geriatric

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.

Administration

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

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

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% (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)

ALERT: U.S. Boxed Warning

Congestive heart failure:

Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of rosiglitazone and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain; dyspnea; and/or edema). If these signs and symptoms develop, manage the heart failure according to current standards of care. Furthermore, consider discontinuation or dose reduction of rosiglitazone.

Rosiglitazone is not recommended in patients with symptomatic heart failure. Initiation of rosiglitazone in patients with established New York Heart Association (NYHA) class III or IV heart failure is contraindicated.

Myocardial infarction:

A meta-analysis of 52 clinical trials (mean duration, 6 months; 16,995 total patients), most of which compared rosiglitazone with placebo, showed rosiglitazone to be associated with a statistically significant increased risk of myocardial infarction (MI). Three other trials (mean duration, 46 months; 14,067 total patients) comparing rosiglitazone with some other approved oral antidiabetic agents or placebo showed a statistically nonsignificant increased risk of MI and a statistically nonsignificant decreased risk of death. There have been no clinical trials directly comparing the cardiovascular risk of rosiglitazone and pioglitazone, another thiazolidinedione, but in a separate trial, pioglitazone (when compared with placebo) did not show an increased risk of MI or death.

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. 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. In the US, initiation of therapy is contraindicated in patients with NYHA class III or IV heart failure; in Canada, use is contraindicated in patients with any stage of heart failure (NYHA class I, II, III, IV). 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.

Disease-related concerns:

• 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.

Special populations:

• 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.

Other warnings/precautions:

• Triple therapy: Canadian labeling does not indicate use of rosiglitazone in combination with both metformin and a sulfonylurea (ie, triple therapy).

Monitoring Parameters

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

C

Pregnancy Considerations

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. Due to long-term safety concerns associated with their use, thiazolidinediones should be avoided in women of reproductive age (Fauser 2012).

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 2015; 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 2015; Blumer 2013; Kitzmiller 2008). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (Kitzmiller 2008)

Other agents are currently recommended to treat diabetes in pregnant women (ACOG 2013; Blumer 2013); rosiglitazone should not be used for the treatment of PCOS (Legro 2013).

Patient Education

• 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, 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, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), bone pain, vision changes, loss of strength and energy, dysphagia, tachycardia, signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), or signs of a heart attack (angina; pain in arms, back, neck, jaw, or stomach; shortness of breath; cold sweats; severe dizziness; passing out; 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 healthcare 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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