Glitazones for diabetes

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 concerns
September 2010: Due to cardiovascular safety concerns, rosiglitazone (brand names Avandia, Avandamet) is withdrawn from clinical use in Europe.

This decision follows a Europe-wide review of the risks and benefits of medicines containing rosiglitazone, which concluded that the benefits of treatment no longer outweigh the risks. The review was triggered by new studies showing that rosiglitazone is associated with an increased risk of cardiovascular disorders, including heart attacks and heart failure.

The conclusion of the Europe-wide review is consistent with advice that the MHRA received from the Commission on Human Medicines, which stated that scientific evidence shows that rosiglitazone is associated with an increased risk of cardiovascular disorders. The Commission on Human Medicines is an independent committee responsible for providing expert advice on drug safety.

Please see our web statement on the withdrawal of rosiglitazone, a link to current advice from the National Institute for Health and Clinical Excellence (NICE) and further information for patients.

MHRA web statement on recommended withdrawal of rosiglitazone from clinical use
NICE guidance
Q&A document for patients regarding rosiglitazone withdrawal (63Kb)

Below is a summary of the evidence that led to the decision for withdrawal, and a chronology of previous regulatory action as a result of the continual monitoring of cardiovascular safety.

As of July 2010, an ongoing Europe-wide review of the risks and benefits of rosiglitazone (external link) was initiated due to concerns about cardiovascular safety. This review follows new published data that raise concern about an increased risk of cardiovascular adverse effects of rosiglitazone. These data add substantially to existing evidence and point towards an increased cardiovascular risk with rosiglitazone compared with both placebo and with pioglitazone.

European Medicines Agency update on ongoing benefit-risk review of Avandia and Avandamet

Healthcare professionals are reminded to closely observe the current contraindications and monitoring requirements for rosiglitazone, and to consider alternative treatments where appropriate.

Further information for healthcare professionals has been circulated via the Central Alerting System (CAS). The most recent information issued by the MHRA was :

Information on rosiglitazone and cardiovascular risk circulated on 26 July 2010 via CAS (97Kb)

Patients are reminded of the importance of attending their routine appointments to monitor their diabetic care.

Further information for patients is provided in this Q&A document (28Kb)

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. 

A Europe-wide review in 2006 of the available data from clinical trials had provided new data about the risk of heart failure in patients taking rosiglitazone but had also suggested that patients on rosiglitazone may be at an increased of ischaemic heart disease (eg heart attack). The product information was updated to reflect the findings of this review including addition of information on the risk of ischaemic heart disease.

A publication by Nissen and Wolski (N Eng J Med 2007; 256: 1-15) raised concerns about the cardiovascular safety of rosiglitazone and in particular the risk of myocardial infarction (heart attack). These concerns led to a Europe-wide review in 2007 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 (358Kb).

Below is 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 (EMA) 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 has been updated to include warnings about the risk of myocradial infarction and also to advise 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.

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

EMEA recommends new warnings and contraindications for rosiglitazone (external link)

See also Stop Press article in Drug Safety Update February 2008 (91Kb)

Bladder cancer concern (July 2011)
A European review has found that the use of pioglitazone is associated with a small increased risk of bladder cancer. Healthcare professionals should be aware of new warnings and precautions for use in at-risk patients.

• Pioglitazone should not be used in patients with a history of, or current, active bladder cancer or in patients with uninvestigated visible blood in the urine.
• Before starting pioglitazone, the following known risk factors for development of bladder cancer should be assessed in individuals:
• • if the patient is elderly (the risk of bladder cancer increases with age)
  • current or past history of smoking
  • exposure to some occupational or chemotherapy agents such as cyclophosphamide
  • previous irradiation of the pelvic region.

Patients receiving pioglitazone should immediately report any visible blood in their urine or bladder problems such as pain while urinating or urgency to urinate, to their doctor.

The review also concluded, however, that the benefits of pioglitazone continue to outweigh the risks for those patients who respond to treatment and in whom there are no identified risk factors for bladder cancer. Patients should not stop taking pioglitazone without consulting their doctor.

Please see the following communications on this issue:

MHRA web statement on risk of bladder cancer with pioglitazone (July 2011)

Letter on pioglitazone sent to healthcare professionals in July 2011 (77Kb)

European Medicines Agency press release on pioglitazone (July 2011) (external link)

Drug Safety Update article: Pioglitazone: risk of bladder cancer (August 2011)

The European review concluded that the originator company and all subsequent marketing authorisation holders for pioglitazone-containing medicines should distribute educational materials to relevant healthcare professionals advising of the bladder cancer risk. Please see the link below to a set of model educational materials approved by the MHRA.

Prescribers guide for use with pioglitazone (959Kb)

Marketing authorisation holders should note the specific requirements for distribution of educational materials in the UK and should contact MHRA for advice as necessary.

Email: info@mhra.gsi.gov.uk


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 Product Characteristics, and patients should refer to the patient information leaflet that is given with these medicines.