Avandia (rosiglitazone maleate)

• Class: thiazolidinedione
• For: Type 2 diabetes, for use as monotherapy (that is, with no other diabetes medications) or in combination therapy with metformin or sulfonylurea pills. The use of Avandia (rosiglitazone maleate) in combination therapy with insulin is also indicated.
• Route of Administration: oral
• Action: Insulin sensitizer
• Manufacturer: GlaxoSmithKline (formerly SmithKline Beecham)
• Status: Approved in US and Europe, in a total of at least 26 countries. (It was recommended for approval in March, 2000, by the Europe’s CPMP following an appeal to the EMEA which had rejected rosiglitazone in October 1999.)
• Dose: 4 mg daily; if no improvement within 12 weeks, can increase to 8 mg daily. May be taken with or without meals.
• Available as: 2 mg, 4 mg, and 8 mg tablets. Also available in a combination pill with metformin (Avandamet) and with Amaryl (Avandaryl).
• Action: improves the action of the liver, muscles, and fat tissues (functions as an "insulin sensitizer")
• Side Effects: Fluid retention, congestive heart failure (CHF), liver disease, increased risk of fractures in women (see below); possibly of heart attacks (see below).
• Information for Patients: (From the USPI, March, 2003.)

  Patients should be informed of the following: Management of type 2 diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type 2 diabetes, but in maintaining the efficacy of drug therapy.

  It is important to adhere to dietary instructions and to regularly have blood glucose and glycosylated hemoglobin tested. Patients should be advised that it can take 2 weeks to see a reduction in blood glucose and 2 to 3 months to see full effect. Patients should be informed that blood will be drawn to check their liver function prior to the start of therapy and every 2 months for the first 12 months, and periodically thereafter. Patients with unexplained symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should immediately report these symptoms to their physician. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on AVANDIA should immediately report these symptoms to their physician.

  AVANDIA can be taken with or without meals.

  When using AVANDIA in combination with other hypoglycemic agents, the risk of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.

  Therapy with AVANDIA, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking AVANDIA (see PRECAUTIONS, Pregnancy, Pregnancy Category C). Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies so the frequency of this occurrence is not known.

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  In August, 2007, the FDA announced the manufacturers of Avandia and Actos have agreed to add a stronger warning on the risk of heart failure, a condition that occurs when the heart does not adequately pump blood. The information will be included in the form of a "boxed" warning - FDA's strongest form of a warning. The upgraded warning emphasizes that the drugs may cause or worsen heart failure in certain patients. See Manufacturers of Some Diabetes Drugs to Strengthen Warning on Heart Failure.

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  In May, 2007, the FDA stated that safety data from controlled clinical trials have shown that there is a potentially significant increase in the risk of heart attack and heart-related deaths in patients taking Avandia. However, other published and unpublished data from long-term clinical trials of Avandia… provide contradictory evidence about the risks. See FDA Issues Safety Alert on Avandia.

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  In February, 2007, the manufacturer announced that a study had shown an increased risk of broken bones in women. The letter may also be found at the FDA's website: Clinical Trial Observation of an Increased Incidence of Fractures in Female Patients Who Received Long-Term Treatment with Avandia® (rosiglitazone maleate) Tablets for Type 2 Diabetes Mellitus [PDF file].]

  The label dated March 2003 included an indication for use with insullin. The previous Avandia label (February 2001), under the topic of "Cardiac Failure and Other Cardiac Effects" (in the WARNINGS section), stated "The use of Avandia (rosiglitazone maleate) in combination therapy with insulin is not indicated". This label indicated that, in two 26-week US trials, 611 subjects who had type 2 diabetes and a high prevalence of preexisting medical disorders (including a 2.5% prevalence of CHF), were studied in a comparison of rosiglitazone plus insulin vs. insulin therapy alone. An increased incidence of cardiac failure and other cardiovascular adverse events was seen in patients on rosiglitazone and insulin, compared to patients on insulin and placebo. Patients who experienced heart failure were on average older, had a longer duration of diabetes, and were mostly on the higher 8mg daily dose of rosiglitazone. Three of the 10 patients who developed cardiac failure had no known prior evidence of CHF or preexisting cardiac condition.

• Other drugs in same class: pioglitazone; troglitazone (now withdrawn from the market because of liver problems).

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