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Data Affirms Avandia (Rosiglitazone maleate) Cardiovascular Safety Profile

PHILADELPHIA and LONDON, May 30, 2007 /PRNewswire-FirstCall/ -- GlaxoSmithKline today confirms that a letter to the editor summarizing additional Avandia cardiovascular safety data from several large-scale clinical trials was published online today in The Lancet. This letter, written by Ronald L. Krall, MD, Chief Medical Officer of GlaxoSmithKline, provides the necessary context and clarifies the safety record of Avandia, which is based on sound science and backed by one of the largest research programs ever in diabetes.

    Key data points include:

    -- The recent meta-analysis published in New England Journal of Medicine,

       which has been widely cited in media reports, omitted the total

       percentage number of events.  The actual number of heart attacks

       represents a very low frequency of events - 0.6% for both Avandia and

       the control group (Avandia 86/14,371; control 72/11,634).

    -- Further analyses from ADOPT and DREAM - two long-term prospective

       clinical trials - show that the incidence of ischemic cardiovascular

       events with Avandia is comparable to the two gold standard medicines

       used to treat type 2 diabetes (metformin or a sulfonylurea) in the

       ADOPT study, and to placebo in the DREAM study.

    -- Findings from a soon-to-be-published study, using a managed care

       database of more than 30,000 diabetes patients in a real-world setting,

       show the incidence of hospitalizations for heart attack, and/or for a

       surgery known as revascularization for patients on Avandia is the same

       as for other diabetes treatments.

    -- The independent safety monitoring board for the RECORD trial - a large,

       long-term clinical trial, which has been designed to look at

       cardiovascular outcomes in people with diabetes - reviewed an interim

       analysis of cardiovascular endpoints in all study participants, and

       determined that the study should be allowed to continue.

To summarize, data from long-term, large-scale, prospective clinical trials show that the overall ischemic cardiovascular safety profile, including cardiovascular death, among diabetes patients treated with Avandia is comparable to patients treated with two other widely used diabetes medicines. Avandia is an effective medicine that is an important treatment for millions of patients who are using it to manage their diabetes, a disease with potentially devastating consequences if left unmanaged.

Diabetes is at epidemic proportions, and GlaxoSmithKline believes that a balanced and responsible approach to assessing the risks and benefits of all available treatments is in the best interests of patients and everyone with a stake in treating this disease successfully.

    UK Media inquiries:                  Phil Thomson      (020) 8047 5502

                                         Joss Mathieson    (020) 8047 5502

                                         Gwenan White      (020) 8047 5502

    US Media inquiries:                   Nancy Pekarek     (215) 751 7709

                                          Mary Anne Rhyne   (919) 483 2839

                                          Alice Hunt        (215) 751 7709

    US Analyst/ Investor inquiries:       Frank Murdolo     (215) 751 7002

                                          Tom Curry         (215) 751 5419

    European Analyst/Investor inquiries:  Anita Kidgell     (020) 8047 5542

                                          David Mawdsley    (020) 8047 5564

                                          Sally Ferguson   (020) 8047 5543

[Avandia is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. Avandia is indicated as monotherapy and in combination with a sulfonylurea, metformin, or insulin when diet, exercise, and a single agent do not result in adequate glycemic control. Avandia is also indicated for use in combination with a sulfonylurea plus metformin when diet, exercise, and both agents do not result in adequate glycemic control.

Avandamet is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with dual rosiglitazone and metformin therapy is appropriate.

Avandaryl is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with dual rosiglitazone and glimepiride therapy is appropriate.

Important Clinical Considerations When Prescribing AVANDIA(R) (rosiglitazone maleate), AVANDAMET(R) (rosiglitazone maleate/metformin HCl) or AVANDARYL(TM) (rosiglitazone maleate and glimepiride)


    -- Patients with congestive heart failure, as rosiglitazone may exacerbate

       congestive heart failure


    -- Renal disease or renal dysfunction (based on serum creatinine levels

       Greater Than or Equal To 1.5 mg/dL in males, Greater Than or Equal To

       1.4 mg/dL in females)

Avandamet should not be initiated in patients Greater Than or Equal To 80 years of age unless creatinine clearance is normal. Temporarily discontinue Avandamet at the time of or prior to procedures involving intravascular iodinated contrast materials. Withhold Avandamet for 48 hours post procedure and reinstitute only after normal renal function has been established.

-- Acute or chronic metabolic acidosis, including diabetic ketoacidosis

Withhold therapy in the presence of any condition associated with hypoxemia, dehydration, or sepsis.


    -- Diabetic ketoacidosis, with or without coma. This condition should be

       treated with insulin

    Boxed WARNINGS:

    For Avandia, Avandamet and Avandaryl: CONGESTIVE HEART FAILURE

    -- Thiazolidinediones, including rosiglitazone, cause or exacerbate

       congestive heart failure. This risk is higher with concomitant use of

       insulin or a sulfonylurea

    -- After initiation of rosiglitazone, and after dose increases, observe

       patients carefully for rapid weight gain, significant edema, or other

       signs of congestive heart failure, and discontinue rosiglitazone if any

       of these signs occur

    -- Do not initiate or continue AVANDIA, AVANDAMET, or AVANDARYL in

       patients with congestive heart failure. Continuation of rosiglitazone

       in patients who develop congestive heart failure may result in death


Lactic acidosis is a rare but serious metabolic complication that can occur due to metformin accumulation during therapy with Avandamet

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is approximately 0.03 cases/1000 patient-years and may be fatal in approximately 50% of cases. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. This risk may be significantly decreased by regular monitoring of renal function in patients taking Avandamet and by use of the minimum effective dose. Patients with congestive heart failure requiring pharmacologic management are also at increased risk of lactic acidosis.

The onset of lactic acidosis often is subtle and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

Patients should be cautioned against excessive alcohol intake when taking Avandamet. Avandamet should be temporarily discontinued prior to surgical procedures, specifically those involving restricted intake of food and fluids.



    -- The UGDP trial found that tolbutamide, a sulfonylurea, was associated

       with increased risk of cardiovascular mortality. Glimepiride was not

       studied in this trial; however, it is prudent to consider that this

       warning may apply to all sulfonylureas


    -- Rosiglitazone, like other thiazolidinediones, is associated with fluid

       retention (which can lead to or exacerbate heart failure) and edema

    -- In addition, a higher incidence of other cardiovascular events was

       observed when rosiglitazone was added to insulin


    -- Check liver enzymes prior to initiation of Avandia, Avandamet, or

       Avandaryl and periodically per clinical judgment

    -- Avandia, Avandamet, and Avandaryl should not be started in patients

       with active liver disease or with ALT levels >2.5X the upper limit of


    -- Postmarketing reports of hepatitis and ALT >3X the upper limit of

       normal have been received for rosiglitazone. Very rarely, these reports

       have involved hepatic failure with and without fatal outcome, although

       causality has not been established


    -- Since impaired hepatic function has been associated with some cases of

       lactic acidosis, Avandamet should generally be avoided in patients with

       clinical or laboratory evidence of hepatic disease


    -- Postmarketing reports of new onset or worsening macular edema have been

       received for patients taking rosiglitazone or another

       thiazolidinedione. In some cases, patients' symptoms improved following

       discontinuation of their thiazolidinedione

    -- An increased incidence of bone fracture has been observed in women

       taking rosiglitazone. The majority of the fractures were reported in

       the upper arm (humerus), hand, and foot

    -- Anemia, hypoglycemia, resumption of ovulation, and weight gain


    -- As with all sulfonylureas, severe hypoglycemia may occur. Elderly,

       debilitated, or malnourished patients, or patients with adrenal,

       pituitary, renal, or hepatic insufficiency may be more sensitive to the

       glucose-lowering effect of sulfonylureas and should be started on

       Avandaryl 4 mg/1 mg. If hypoglycemia occurs, a reduction in the dose of

       the sulfonylurea component may be necessary]

CONTACT: UK Media, Phil Thomson, +020-8047-5502, or Joss Mathieson,+020-8047-5502, or Gwenan White, +020-8047-5502, or US Media, NancyPekarek, +1-215-751-7709, or Mary Anne Rhyne, +1-919-483-2839, or AliceHunt, +1-215-751-7709, or US Analysts and Investors, Frank Murdolo,+1-215-751-7002, or Tom Curry, +1-215-751 5419, or European Analysts andInvestors, Anita Kidgell, +020-8047-5542, or David Mawdsley,+020-8047-5564, or Sally Ferguson, +020-8047-5543, all of GlaxoSmithKline

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Posted: May 2007