Overnight the European Medicines Agency (EMA) has recommended the suspension of the marketing authorisations for the anti-diabetes medicine Avandia (Rosiglitazone). These medicines will stop being available in Europe within the next few months. In Australia roziglitazone requires an authority to be obtained on the PBS and is only available to patients with type 2 diabetes whose blood glucose concentrations are inadequately controlled (HbA1c > 7%) as dual oral therapy with metformin or a sulfonylurea when combination therapy with metformin and a sulfonylurea is contraindicated or not tolerated. The Australian Product Information includes a boxed warning stating that: ‘The use of Avandia is not recommended in patients with known ischaemic heart disease, particularly in those taking nitrates. Avandia has been shown to be associated with an increased risk of myocardial ischaemia (angina, infarction).’ Rosiglitazone (Avandia). Earlier this month the British Medical Journal published an investigation into Avandia.
Below is a link to the EMA statement:
A simultaneous decision to significantly restrict access to the drug has been taken by the FDA in the US:
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Professor Nikolai Petrovsky is Director of Endocrinology at Flinders Medical Centre/Flinders University.
“What is the likelihood that the marketing approval for rosiglitazone (Avandia) will now be withdrawn in Australia? Whilst the FDA have recently voted to allow rosiglitazone to remain available in the US albeit with additional cardiovascular warnings on its label, the European Medicines Agency has gone one step further and is planning to withdraw the marketing authorisation for rosiglitazone in Europe. Overall, the Australian TGA tends to follow the European Agency more than FDA so it will be interesting to see where it goes in this instance. Of course the exercise in withdrawing the marketing approval for rosiglitazone is now largely academic anyway as most diabetes clinicians and patients have already voted with their feet and moved to alternative glucose lowering medications, presumed not to share the cardiovascular problems ascribed to rosiglitazone. Even for those patients who have had a major benefit from rosiglitazone treatment there is the ready alternative to switching to pioglitazone, a drug in the same class as rosiglitazone but whose image hasn’t been tarnished to the degree of rosiglitazone. Another reason for the fall in rosiglitazone usage over recent years has been the introduction of several new classes of diabetes medication including the GLP-1 agonists and DP4 inhibitors which offer similar glucose lowering. So whether rosiglitazone has been being unfairly treated or not, the market has already spoken leaving rosiglitazone with a limited future as a mainstay diabetes medication.”
Assoc. Prof. Richard O’Brien is a Senior Endocrinologist at the Austin Hospital and Clinical Dean of Medicine at the Austin and Northern Clinical Schools, University of Melbourne
“Avandia (rosiglitazone) has been available for several years for the treatment of type 2 diabetes. It belongs to a class known as thiozoladinediones (TZD’s), the other member of which is pioglitazone (Actos), that act to enhance the effectiveness of the body’s natural insulin. These medications are very effective in some, but not all, people with type 2 diabetes. In 2007 a meta-analysis of several rosiglitazone trials was published, that suggested that rosiglitazone treatment may be associated with an increased risk of myocardial infarction (heart attack). This resulted in the use of rosiglitazone being restricted in many countries including Australia. No such concerns have been raised with the alternative medication, pioglitazone.
There have been many subsequent studies, some confirming the results of the meta-analysis, some showing no increase in heart attack risk. The only trial specifically designed to examine cardiovascular safety, RECORD, published last year, did not show an increase in cardiovascular risk.
Medical experts have been divided on the issue but some, such as Stephen Nissan, the author of the original meta-analysis, have been very vocal in demanding that rosiglitazone be taken off the market. There has also been political pressure, with some USA senators questioning the safety of the drug.
My own personal view is that the data suggesting an increased heart attack and stroke risk with rosiglitazone are unconvincing. However, given that an alternative agent, pioglitazone, is available, it is perhaps not surprising that the regulators in Europe have acted to withdraw rosiglitazone. In the USA, regulators have severely restricted its use to patients with low cardiovascular risk who are already taking the drug, or to new patients who are not able to take pioglitazone.
Given that Australian regulators pay close attention to the decisions of their counterparts in Europe and the USA, they may soon make a decision to alter the availability of rosiglitazone here. Patients currently taking rosiglitazone need not be alarmed. They should not stop taking their medication, but if they have concerns, they should consult their doctor. “
These opinions are those of the author and not of the Austin Hospital nor the University of Melbourne
Prof. O’Brien has, in the past, received lecture fees and consulting fees from GSK, makers of rosiglitazone, and lecture fees from Eli Lilly, makers of pioglitazone.
Dr Agnes Vitry is a Senior Research Fellow at the Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, University of South Australia
”I agree with the European Medicines Agency (EMA)’s decision to suspend Avandia’s marketing authorization as there are serious concerns about the cardiovascular safety of this diabetes medicine. The whole point of controlling blood sugar in people with diabetes is to prevent macrovascular adverse events such heart attacks and microvascular adverse events such as blindness. With no evidence that Avandia provides these benefits but with strong concerns about the opposite (increased risk of cardiovascular morbidity and mortality), there is no point keeping such a medicine on the market!
Although Avandia is much less used in Australia than in the United States and some European countries owing to the PBS restrictions, it is still too much used and I hope that the Therapeutics Good Administration (TGA) will follow the EMA’s leadership and withdraw this medicine from the Australian market.
It is important that lessons are learnt from Avandia’s story for improving the medicine regulatory framework. It is a concern that medicines used for prevention of serious diseases are still approved on the basis of surrogate outcomes such blood sugar levels. It is particularly important when medicines such diabetes medicines are used by millions of people shortly after marketing approval. It may expose numerous patients to the risk of serious adverse effects that may be unknown at the time of marketing but with no guarantee that they may benefit in the long term from reduced risk of diabetes complications. Medicine regulatory agencies such as the TGA must strengthen the marketing approval requirements to ensure a higher protection of the public.”
Comments from the UK Science Media Centre:
Donald RJ Singer, Professor of Clinical Pharmacology and Therapeutics, British Pharmacological Society, said:
“People with diabetes are at increased risk of cardiovascular disease. Despite lowering blood sugar, there is increasing concern that the tablet treatment for Type 2 diabetes rosiglitazone may in fact increase risk of heart failure and other serious cardiovascular disorders.
“Both the European Medicines Agency (EMA) and the US drugs regulator, the Food and Drug Administration (FDA) have today issued important new guidance placing major restrictions on the use of rosiglitazone. The EMA recommended suspension of the drug throughout Europe, either as separate treatment or in combination tablets.
“The FDA has been less cautious, in allowing restricted availability of rosiglitazone to patients with Type 2 diabetes who are not able to tolerate other tablet treatments and would otherwise need to move on to insulin injections. It is interesting that the EMA has not yet taken the definitive step of complete withdrawal of the drug. However high quality evidence is needed to convince the EMA about justification of a future limited clinical licence for sub-groups of Type 2 diabetics in whom the benefits of rosiglitazone may outweigh its potential cardiovascular risks.
“It is very important that patients on rosiglitazone seek medical advice before changing treatment so that their condition remains well-controlled as their diabetic regime is adjusted. As advised by the MHRA for the UK in July, in countries where rosiglitazone is still available, it remains important that patients already at increased risk from heart failure or coronary disease seek medical advice as soon as possible to change to more appropriate treatment.
“The recent experience with rosiglitazone points to the need for rigorous clinical trials to ensure that the best quality studies are available at the earliest possible stage, to make sure that, for drugs in clinical use, the benefits of treatment outweigh any risks. This is both particularly challenging and important for conditions like diabetes in which patients are already at high risk of complications from the underlying medical disorder.”
Dr Terry Maguire, community pharmacist and former member of Committee on Safety of Medicines, said:
”It’s no great surprise that the EMA have taken this decision today, as the weight of evidence suggesting that the long term risks associated with Avandia use outweighed the benefits was compelling. Certainly regulators and pharmaceutical manufacturers should learn lessons for this episode that will have left the public and health professionals concerned and a little confused about the licensing arrangements in the UK. I would remind patients that they should now follow the advice of their medical practitioner or pharmacist regarding what action they should take personally if they are currently taking Avandia.”
Dr Anthony Cox, Lecturer in Clinical Therapeutics at Aston Pharmacy School, said:
”Rosiglitazone’s withdrawal from the European market was inevitable given the evidence of harm from cardiovascular events and its limited benefits. There are lessons here about the whole process of drug regulation, from licensing to monitoring the drug once on the market and the role of the pharmaceutical industry in trial design and data collection. The public perception of the pharmaceutical industry is important, as events that undermine trust are a public health concern.
”As an aside, while the EMA has been accused of being less open, in terms of decision making, than the US regulator, the decision of the FDA to allow the drug remain on the market using a restricted access process to control risk is surprising, and in the long term unlikely to be sustainable.
”People taking rosiglitazone should not panic; while important, the risks are small to the individual in the short-term, and they should consult with their medical practitioner or pharmacist before taking any action.”
Professor Kent Woods, Chief Executive of the Medicines and Healthcare products Regulatory Agency (MHRA), said:
”Patient safety is the top priority for the MHRA and we have been constantly monitoring the situation regarding rosiglitazone. Today’s suspension means that clinicians should review all patients currently on rosiglitazone and take appropriate action, according to the individual clinical situation, to change to another suitable treatment.”