The Drug News column generally reviews new medications approved by the Food and Drug Administration (FDA) and relevant to the clinical applications of advanced practice nurses. However, in some cases, postapproval monitoring and evaluation of drugs indicate a need for notifying clinicians and the public of identified concerns associated with drug prescribing or use. These notifications may be in the form of black box, black label, or boxed warnings (See Boxed Warning Situations).
Rosiglitazone (Avandia) was developed by GSK and approved by the FDA in May 1999 as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1 In April 2002, rosiglitazone received a new warning about an increased risk of heart failure.2 In December 2005, the FDA and GSK notified providers of reports of new or worsening diabetic macular edema in patients taking the drug. By February 2007, GSK notified healthcare professionals of a significantly higher risk of fracture in women who received rosiglitazone compared to those receiving metformin or glyburide. In May 2007, reports circulated describing the effects of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.3-5 This same month, the FDA News published "FDA Issues Safety Alert on Rosiglitazone (Avandia)" for immediate release.6
Background
The active ingredient in rosiglitazone increases insulin sensitivity while reducing circulating insulin levels. Six specific changes were made by GSK to the following sections of the prescribing information for rosiglitazone: 1) the boxed warning for congestive heart failure and myocardial ischemia, 2) indications and usage, 3) contraindications, 4) warnings and precautions for cardiac failure, 5) warnings and precautions for myocardial ischemia, and 6) warnings and precautions for fractures.
Mechanism of Action
A member of the thiazolidinedione class of antidiabetic agents, rosiglitazone improves tissue sensitivity to insulin and inhibits hepatic gluconeogenesis. Thiazolidinedione class drugs work through activation of the peroxisome proliferator-activated nuclear receptors (PPAR). The three PPAR subtypes are found in genes that are involved in lipid metabolism and energy homeostasis, including lipid storage or catabolism, fatty acid transport, uptake, and intracellular binding. The subtype peroxisome proliferator-activated nuclear receptor-gamma is integral in glucose metabolism via the enhancement of insulin sensitivity.7,8 PPAR receptors are found in adipose tissue, skeletal muscle, and the liver.
Insulin resistance is a common feature characterizing the pathogenesis of type 2 diabetes. In three mouse animal models, rosiglitazone has been shown to reduce blood glucose and hyperinsulinemia.9
Adverse Reactions
Rosiglitazone can cause fluid retention. Patients with New York Heart Association (NYHA) Class I or II heart failure (ejection fraction of 45% or less) have an increased risk of cardiovascular events.10 Rosiglitazone is contraindicated in patients with established NYHA Class III or Class IV heart failure.9
Patients taking a combination of rosiglitazone and insulin should be monitored closely for cardiovascular adverse events. Combination therapy should be discontinued after 4 to 5 months if the patient fails to demonstrate an adequate hemoglobin A1C reduction or development of any significant adverse event.10
Adverse reactions during rosiglitazone monotherapy include anemia (1.9%) and edema (4.8%).10 In combination therapy with sulfonylureas, episodes of dose-related, mild-to-moderate hypoglycemia were reported.9,10 In double-blind clinical trials with rosiglitazone as monotherapy, adverse reactions (greater than 5%) included upper respiratory track infection, injury, headache, back pain, hyperglycemia, fatigue, sinusitis, diarrhea, and hypoglycemia. Adverse events in combination with sulfonylurea or metformin were similar to those during monotherapy. In pediatric patients, the most common adverse event with monotherapy rosiglitazone was headache, occurring in 17.2%.9, 10
Special Instructions
The FDA has decided to keep rosiglitazone on the market while the safety assessment continues. Specific instructions related to rosiglitazone prescribing include:
* Patients on insulin should not receive doses of rosiglitazone greater than 4 mg daily.9,10
* Drug interactions include inhibitors of the cytochrome P450 isoform CYP2C8, such as gemfibrozil, which may increase rosiglitazone serum levels, or inducers of CYP2C8, such as rifampin, which may decrease rosiglitazone serum levels.
* Rosiglitazone is a pregnancy Category C medication and should not be used during pregnancy.9,10
* Rosiglitazone should not be used in patients with clinical evidence of liver disease or elevated serum transaminase levels (alanine aminotransferase over 2.5 times upper limit of normal) at the start of rosiglitazone therapy.9,10
* Rosiglitazone was more effective in reducing fasting plasma glucose and hemoglobin A1C when administered in divided doses two times a day compared to once a day.
* Fluid retention should be monitored as weight gain, macular edema, and heart failure may occur.
* Female patients should be monitored for bone fracture.
The revision of rosiglitazone's existing boxed warning includes findings from a meta-analysis of 42 clinical studies and three additional studies (see Boxed Warning for Rosiglitazone).
Boxed Warning Situations12
A boxed warning is ordinarily used to highlight for prescribers one of the following situations:
* There is an adverse reaction so serious in proportion to the potential benefit from the drug (such as a fatal, life-threatening or permanently disabling adverse reaction) that it must be considered in assessing the risks and benefits of using a drug.
* There is a serious adverse reaction that can be prevented or reduced in frequency or severity by appropriate use of the drug (such as patient selection, careful monitoring, avoiding certain concomitant therapy, addition of another drug or managing patients in a specific manner, avoiding use in a specific clinical situation).
* The FDA approved the drug with restrictions to assure safe use because it concluded that the drug can be safely used only if distribution or use is restricted (such as under 21 CFR part 314, subpart H, [S] 314.520 "Approval with restrictions to assure safe use").
Boxed Warning for Rosiglitazone9,11
WARNING: CONGESTIVE HEART FAILURE AND MYOCARDIAL ISCHEMIA
Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients. After initiation of Avanida, 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, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of Avandia must be considered.
Avandia is not recommended in patients with symptomatic heart failure. Initiation of Avandia in patients with established NYHA Class III or IV heart failure is contraindicated.
A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared Avandia to placebo, showed Avandia to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 total patients) comparing Avandia to some other approved oral antidiabetic agents or placebo have not confirmed or excluded this risk. The available data on the risk of myocardial ischemia are inconclusive.
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