Restrictions on the use of rosiglitazone Restricted access programme and additional contraindications required to minimise cardiovascular risks

HSA is working with GlaxoSmithKline (GSK) to implement restrictions on the use of rosiglitazone in Singapore following the review of additional data about its associated cardiac ischaemic risks made available since our earlier review in 2007. Healthcare professionals will receive more information on the restricted access programme once the details have been finalised.

Rosiglitazone (Avandia®, GSK) is an oral agent for the treatment of type 2 diabetes mellitus. It belongs to the thiazolidinediones class of drugs and has been registered by HSA since 2000 for use as an adjunct to diet and exercise; as monotherapy or in combination with metformin or a sulfonylurea to reduce insulin resistance and lower elevated blood glucose in patients with type 2 diabetes mellitus. Rosiglitazone is also present in two other medicinal products registered in Singapore – Avandamet® (rosiglitazone and metformin) and Avandaryl® (rosiglitazone and glimepiride). To date, Avandaryl® is not marketed locally.

HSA's assessment of cardiovascular (CV) risk associated with rosiglitazone

On 24 September 2010, HSA issued a Dear Healthcare Professional Letter to inform about the new restriction on the use of rosiglitazone. This recommendation arose after an in-depth review, in consultation with the HSA Pharmacovigilance Advisory Committee (PVAC) and an expert panel of cardiologist and endocrinologists. The review took into consideration the findings of the various scientific analyses, including data from meta-analyses (Nissen and Wolski ^1,2 , GSK ^3,4, US Food and Drug Administration ^5,6), clinical trials, and observational studies. While the data available 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 placebo.⁷ Based on the recommendations of PVAC and the experts, HSA decided to implement additional restrictions to significantly limit the use of rosiglitazone to a group of patients who are unable to effectively control their blood glucose despite use of alternative anti-diabetic medications. This is to minimise the possible CV risks associated with the use of this drug.

Actions taken by other regulatory agencies

(A) US Food and Drug Administration (FDA)⁸
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 for treatment with rosiglitazone.

FDA is also requiring a re-adjudication of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes (RECORD) trial. This re-evaluation of data is to provide additional clarity about the findings as questions were raised about the potential bias in identification of CV events in this trial in the course of FDA's review

(B) European Medicines Agency (EMA)^9,10
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

HSA's advisory

Based on current available scientific and clinical data, as well as recommendations from 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. However, it was assessed that the availability of rosiglitazone is still essential for a group of patients who cannot effectively control their blood sugar using alternative anti-diabetic medications. To further minimise potential CV risks associated with the use of rosiglitazone, additional contraindications and restrictions would be imposed on the use of the drug.

These restrictions include:

1. Contraindication of rosiglitazone in patients with acute coronary syndrome, ischaemic heart disease, and all classes of heart failure.

2. Restriction of rosiglitazone to third-line usage in mono-, dual or triple oral hypoglycaemic therapy.

3. Recommendation that rosiglitazone is not for use in patients with peripheral arterial disease.

For patients who are currently taking rosiglitazone, their physician may consider continuing treatment with this medication if the benefit-risk ratio is assessed to be favourable. All patients receiving rosiglitazone should be made aware of the potential CV risks.

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 receive rosiglitazone.

Healthcare professionals are strongly advised to adhere to the new recommendations when prescribing rosiglitazone and to monitor patients prescribed rosiglitazone closely for CV-related events. Any serious adverse reactions suspected to be related to rosiglitazone should be reported to HSA's Vigilance Branch.

Reference

1. NEJM 2007; 356(24): 2457-2471

2. Arch Intern Med. 2010;170(14):1191-1201

3. http://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4308s1-03-gsk-steward.pdf

4. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218492.pdf

5. http://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4308s1-00-index.htm

6. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM224738.pdf

7. J Am Coll Cardiol, 2007;49(16): 1696-704.

8. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm226994.htm

9. http://www.ema.europa.eu/ema/index.jsp&curl=pages/news_and_events/news/2010/09/news_detail_001119.jsp&murl=menus/news_and_events/news_and_events.jsp&mid= WC0b01ac058004d5c1

10. http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2010/09/ WC500097003.pdf