Safety Alerts
HSA's advisory on rosiglitazone
Audiences
Healthcare professional
Industry member
Product type
Therapeutic Products
24 September 2010
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The Health Sciences Authority (HSA) has reviewed of the recent scientific analyses conducted to determine the cardiovascular (CV) risk associated with the use of rosiglitazone and concluded on its recommendations on the use of rosiglitazone. The Vigilance Branch, HSA had held discussions with its Pharmacovigilance Advisory Committee (PVAC) together with a panel of experts including endocrinologists and cardiologists to assess the CV risk of rosiglitazone. Based on this assessment, additional restrictions on the use of rosiglitazone will be implemented to significantly limit its use to a group of patients who are unable to effectively control their blood glucose despite use of alternative anti-diabetic medications, in order to minimise any possible CV risks associated with the use of this drug.
Rosiglitazone (Avandia®, GlaxoSmithKline (GSK)) has been registered in Singapore since 2000 and is currently licensed for use as an adjunct to diet and exercise in the treatment of type 2 diabetes mellitus; as monotherapy or in combination with metformin or a sulfonylurea to reduce insulin resistance; and to lower elevated blood glucose in patients with type 2 diabetes mellitus. It is also registered as Avandamet® (GSK), containing a combination of rosiglitazone and metformin and as Avandaryl ® (GSK), containing a combination of rosiglitazone and glimepiride. Avandaryl® is currently not marketed in Singapore. These products are currently contraindicated in patients with New York Heart Association (NYHA) Class III and IV heart failure and restricted in patients with acute coronary events in Singapore.
Cardiovascular risks associated with rosiglitazone
The Vigilance Branch, HSA has reviewed the findings of the various scientific analyses, including data from meta-analyses (Nissen and Wolski1,2, GSK3,4, US Food and Drug Administration5,6), clinical trials, and observational studies. While the data on the CV ischemic risks of rosiglitazone have their limitations and may not be completely definitive, a possible increased risk of myocardial ischaemic events associated with rosiglitazone cannot be excluded. In addition, a review of a placebo-controlled one-year trial in patients with NYHA Class I and II congestive heart failure found a worsening or possible worsening of heart failure occurring in 6.4% of patients treated with rosiglitazone, compared with 3.5% of patients on placebo7.
Summary of main studies reviewed on the CV risks associated with rosiglitazone
Table caption
Type of study | Author/s or name of studies | Findings on CV safety | Remarks |
|---|---|---|---|
Meta-analyses | Nissen & Wolski1,2, GSK 3,4, US FDA 5,6 | Possible increase in CV risk reported. In totality the data suggests a trend of a small increased risk of myocardial infarction when compared to other anti-diabetic agents. No increased risk of CV death was found. | Studies were heterogeneous and involved patients who were drug naïve, on monotherapy, or on combination therapy with other oral anti-diabetic medicines |
Large long term clinical trials that compared rosiglitazone head-on with other anti-diabetic agents | RECORD11 | The study had a pre-specified non-inferiority margin of 1.20 for its hazard ratio (HR). | Designed to investigate CV outcomes with CV death and CV mortality as the primary composite endpoint |
DREAM12, ADOPT13 | Did not find an increased risk of cardiovascular events associated with rosiglitazone. | Not designed primarily to investigate CV outcomes |
International Regulatory Actions Taken
US Food and Drug Administration's (FDA's) actions8
The US FDA had convened an Advisory Committee meeting in July 2010 to review the benefit-risk profile of rosiglitazone and has announced that it would significantly restrict the use of rosiglitazone and would introduce new detailed patient information procedures while it awaits additional information to help further clarify the benefit-to-risk profile of the product. Current users of rosiglitazone may continue with the medication if they are benefiting from it and acknowledge their understanding of the potential risks. New patients will be eligible for rosiglitazone only if they cannot achieve glycemic control with other medications. Doctors will have to attest to and document their patients' eligibility and patients have to review statements describing the CV safety concerns associated with this drug. At the same time, FDA is also requiring a re-adjudication of the RECORD trial, which was a large randomised study of the CV safety of rosiglitazone.
European Medicines Agency's (EMA's) actions9,10
The EMA's Committee for Medicinal Products for Human Use (CHMP) has completed their review on all the available data on the risk of CV problems associated with rosiglitazone. The EMA has decided to suspend marketing authorization of the product until additional data becomes available to help further clarify the benefit-to-risk profile of rosiglitazone. Rosiglitazone-containing products will stop becoming available in Europe within the next few months.
Local Situation
To date, HSA has received 23 adverse drug reaction reports associated with rosiglitazone, of which six reports were CV-related adverse events. Of these six reports, four were coded as myocardial infarction and other two cases were worsening of heart failure and congestive heart failure. In the case of worsening of heart failure, the event was confounded by the pre-existing diagnosis of NYHA Class I/II heart failure.
HSA's assessment and recommendations
Based on current available scientific and clinical data, recommendations of the PVAC and the expert panel of endocrinologists and cardiologists, HSA has assessed that a possible increased risk of myocardial ischaemic events associated with rosiglitazone cannot be excluded (please refer to Annex A). However, for a group of patients who cannot effectively control their blood sugar using alternative medications, the benefits of rosiglitazone may exceed these risks. Hence, additional contraindications and restrictions would be implemented to mitigate any possible CV risks associated with the use of rosiglitazone and these include the following regulatory recommendations:
Contraindication in patients with acute coronary syndome, ischaemic heart disease, and all classes of heart failure (including NYHA Class I/II heart failure patients).
Restriction to third-line usage in mono-, dual or triple oral hypoglycaemic therapy.
Not recommended for use in patients with peripheral arterial disease.
In addition, HSA is working with GSK to develop and implement a programme to ensure that only selected patients who have been assessed by their doctors to be suitable for treatment with rosiglitazone are prescribed it. These patients should also be clearly informed of the benefits and risks associated with their medication. The actual documentary process will be communicated to healthcare professionals shortly.
Healthcare professionals are advised to strongly adhere to the new recommendations for rosiglitazone when prescribing it to their patients. HSA also recommends that patients prescribed rosiglitazone should be monitored more closely for CV-related events.
References
Nissen and Wolski, 2007, Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes, N Engl J Med 356(24), pp2457-2471
Nissen and Wolski, 2010, Rosiglitazone revisited, An updated meta-analysis of risk for myocardial infarction and cardiovascular safety, Arch Intern Med
Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting, July 30, 2007, Presentation by Murray W. Stewart, D.M., F.R.C.P., GlaxoSmithKline
Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting, 13, 14 July 2010, meeting materials, GSK Core
Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting, July 30, 2007, Presentation by Joy Mele, Statistician, Division of Biometrics, US Food and Drug Administration on FDA meta-analysis
Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting, 13, 14 July 2010, FDA briefing information
Dargie, H.J., et al., A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association Functional Class I or II Heart Failure. J Am Coll Cardiol, 2007. 49(16): p. 1696-704.
Home, P.D., et al., Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet, 2009. 373(9681): p. 2125-35.
Gerstein, H.C., et al., Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet, 2006. 368(9541): p. 1096-105.
Kahn, S.E., et al., Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med, 2006. 355(23): p. 2427-43.