Thiazolidinediones, rosiglitazone and pioglitazone

The information below summarises the current safety information for rosiglitazone and pioglitazone. This information should be read alongside the information given in the Summary of Product Characteristics and Patient Information Leaflet for Avandia, Avandamet▼, Actos and Competact▼, which can be found on the website of the European Medicines Agency: 

› European Public Assessment Report for Actos (external link) 
› European Public Assessment Report for Avandia (external link
› European Public Assessment Report for Avandamet▼ (external link) 
› European Public Assessment Report for Competact▼ (external link) 

Cardiovascular safety of rosiglitazone and pioglitazone 
Patients with diabetes are at an increased risk of cardiovascular disorders, including heart failure and ischaemic heart disease, due to the underlying condition. However, thiazolidinediones may cause fluid retention, which in turn may make some heart problems worse or lead to heart failure. Warnings about this risk have been present in the product information since it was authorised in 2000.  Furthermore, the Patient Information Leaflet advises about this potential risk, and patients who are at risk of heart failure should talk to their doctor before they start taking Avandia. 

Further concerns have arisen about the cardiovascular safety of the thiazolidinedione.  Heart failure is a recognised risk of such treatment. More recently it has been suggested that rosiglitazone may be associated with a small increased risk of myocardial infarction (heart attack). These concerns have led to a Europe-wide review of the available data for the safety and efficacy of the thiazolidinediones, including the cardiovascular safety.  

The findings of this European review and advice to healthcare professionals are detailed in a Drug Safety Update article published in December 2007.  

For a summary of the publicly available data on myocardial ischaemic events and death from cardiovascular causes considered in the European review of rosiglitazone and pioglitazone:

› Summary of the publicly available data on myocardial ischaemic events and death from cardiovascular causes considered in the European review of rosiglitazone and pioglitazone (28Kb)   

Following this review the European Medicines Agency has advised that the benefits of both rosiglitazone and pioglitazone in the treatment of type 2 diabetes continue to outweigh their risks. However, the prescribing information will be updated to include a warning that, in patients with ischaemic heart disease (ie, that caused by a reduced blood supply to the heart), rosiglitazone should be used only after careful evaluation of every patient’s individual risk. In addition, the combination of rosiglitazone and insulin should be used only in exceptional cases and under close supervision.  

› EMEA press release: European Medicines Agency confirms positive benefit-risk balance for rosiglitazone and pioglitazone (external link) 

Fracture risk 
Analysis of clinical trial data has identified an increased risk of fracture (mainly in the foot and arm) in women given rosiglitazone or pioglitazone; this analysis did not identify a risk in men. Letters to healthcare professionals were sent in March and April, 2007. 

› Letters to healthcare professionals - March 2007
› Letters to healthcare professionals - April 2007
› Drug Safety Update October 2007

Eye disorders 
New-onset or worsening diabetic macular oedema (swelling of the retina of the eye due to leakage of fluid from blood vessels) with decreased visual acuity has been reported with rosiglitazone and pioglitazone. Many of these patients reported concurrent peripheral oedema (tissue swelling throughout the body). Whether there is a direct association between rosiglitazone or pioglitazone and macular oedema is unclear but healthcare professionals should be alert to the possible of macular oedema if patients report disturbances in visual acuity and should consider appropriate referral to an ophthalmologist.  

Other safety information with rosiglitazone and pioglitazone 

Contraindications
Rosiglitazone and pioglitazone are contraindicated in patients with:

• known hypersensitivity to rosiglitazone or to any of the excipients  
• cardiac failure or history of cardiac failure (NYHA class I to IV) 
• hepatic impairment.

Pioglitazone is also contra-indicated in diabetic ketoacidosis. 

Special warnings and precautions for use
In addition to the current safety information given above, other warnings and special precautions for use with rosiglitazone and pioglitazone include the risk of weight gain, anaemia (or reduction in haemoglobin and haematocrit), and hypoglycaemia (in combination with sulphonylurea or insulin). 

Liver enzymes should be checked before starting treatment with rosiglitazone and pioglitazone in all patients and periodically thereafter based on clinical judgement. 

Rosiglitazone and pioglitazone treatment might cause ovulation to resume in patients who are anovulatory because of insulin resistance. Therefore, these patients may be at risk of pregnancy.  

Rosiglitazone and pioglitazone should be used with caution during concomitant use of medicines that inhibit the CYP2C8 enzyme (e.g. gemfibrozil) or induce it (e.g. rifampicin).  

Rosiglitazone and pioglitazone tablets contain lactose and therefore should not be given to patients with rare hereditary galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. 

Rosiglitazone should be used with caution in patients with severe renal insufficiency   

This is not a complete list of the safety information of rosiglitazone and pioglitazone. For further information healthcare professionals should refer to the Summary of Products Characteristics, and patients should refer to the Patient Information Leaflet that is given with these medicines.