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Q&A: Avandia (rosiglitazone)

On September 23, 2010, the U.S. Food and Drug Administration announced that it would restrict access to rosiglitazone through use of a Risk Evaluation and Mitigation Strategy, or REMS.

Under the Food and Drug Administration Amendments Act of 2007, FDA can require a drug sponsor to issue a REMS to impose certain restrictions to assure that the benefits of a drug continue to outweigh its risks.

General information

Q1. What is rosiglitazone?
Q2. Why is FDA restricting the use of rosiglitazone substantially by requiring a Risk Evaluation and Mitigation Strategy (REMS)?

 

Information for Patients

Q3: What does FDA's decision on rosiglitazone mean for patients currently taking this medication?
Q4. What does FDA's decision for rosiglitazone mean for new patients who are considering taking this medication?
 

Information for Healthcare Professionals

Q5: What does FDA's decision on rosiglitazone mean for healthcare professionals with patients currently taking this medication?
Q6: What does FDA's decision on rosiglitazone mean for healthcare professionals considering putting a patient taking this medication?

 

Other Background Information>

Q7. Why has FDA not removed rosiglitazone from the U.S. market?
Q8: What are international regulators doing about rosiglitazone?
Q9: What additional information on rosiglitazone's safety does FDA hope to obtain?
Q10. FDA is also requiring that the TIDE trial be stopped. What is the TIDE trial and what does it have to do with the safety of rosiglitazone?
Q11: What is FDA doing to better assess diabetes medications in the future?

 

Q1. What is rosiglitazone?

A: Rosiglitazone is a thiazolidinedione (TZD) anti-diabetic agent indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Rosiglitazone is sold as a single-ingredient product under the brand name Avandia. It is also available in combination with other diabetes medications. Rosiglitazone combined with metformin is sold under the brand name Avandamet. Rosiglitazone combined with glimepiride is sold under the brand name Avandaryl.

The other TZD drug available in the United States is pioglitazone, or Actos.

 

Q2. Why is FDA restricting the use of rosiglitazone substantially by requiring a Risk Evaluation and Mitigation Strategy (REMS)?

A: For several years, there have been concerns about the potential for a cardiovascular ischemic risk associated with rosiglitazone. Cardiovascular ischemia is a deficiency of blood flow to tissue usually due to constriction or an obstruction of a blood vessel. These concerns have arisen from multiple data sources, including various meta-analyses and observational studies.

Meta-analyses combine the results of several studies that address a set of related research questions; for example, combining and evaluating the pooled results of clinical trials of diabetes control to look for outcomes of cardiovascular ischemia.

Observational studies evaluate the effects of treatments on a group of patients where the assignment of subjects into the treatment or control group is out of the researcher's control; for example, looking at medical charts of patients who had been on rosiglitazone or pioglitazone.

Although the data that show a cardiovascular risk for rosiglitazone have their limitations, no data source exists to refute them. As such, FDA takes the potential cardiovascular safety concerns with rosiglitazone seriously. FDA has decided, in the interest of patient health, to require additional safeguards and restrictions for the use of this drug through a Risk Evaluation and Mitigation Strategy (REMS). This REMS will be designed to assure that the benefits of rosiglitazone continue to outweigh its risks.

 

Q3: What does FDA's decision for rosiglitazone mean for patients currently taking this medication?

 

A: If you are a patient currently taking rosiglitazone, you should continue taking your medication and consult your healthcare professional. Your health care professional and you may choose to select an alternative medication without the concern for cardiovascular ischemia. It is very important that patients with type 2 diabetes continue to control their blood sugar.

The rosiglitazone REMS does not immediately take effect at the time of this announcement; rather, it will take several months to put the REMS in place.

Once the REMS program is in place, current users of rosiglitazone will only be able to continue using the medication if they acknowledge and document that they understand the risks associated with the drug. FDA believes it important for patients to fully understand the risks and benefits associated with their medications.

We will be providing further information on this REMS program in the coming months.

 

Q4. What does FDA's decision for rosiglitazone mean for new patients who are considering taking this medication?

 

A: If you have type 2 diabetes, you should discuss the appropriate treatment with your healthcare professional.

Once the REMS for rosiglitazone is in place, only patients who cannot achieve control of blood sugar on other medications and who decide not to take the alternative medication pioglitazone for medical reasons will be eligible for rosiglitazone.

 

Q5: What does FDA's decision for rosiglitazone mean for healthcare professionals with patients currently taking this medication?

 

A: FDA's decision allows current users of rosiglitazone to continue using the medication if they appear to be benefiting from it and they acknowledge they understand these risks. However, because of concerns for cardiovascular ischemia, physicians may want to consider switching patients to a different medication.

The rosiglitazone REMS will not immediately take effect at the time of this announcement; rather, it will take several months to put the REMS in place Once the REMS is in place, physicians will need to enroll their patients into the REMS in order for them to continue receiving rosiglitazone.

We will be providing further information on this REMS program in the coming months.

 

Q6: What does FDA's decision for rosiglitazone mean for healthcare professionals considering putting a patient taking this medication?

 

A: .Once the REMS is in place, rosiglitazone will be available to patients not already taking it only if they are unable to achieve glycemic control on other medications and decide not to take pioglitazone for medical reasons. Furthermore, healthcare professionals will have to attest to and document their patient's eligibility if they believe that their patient is a candidate for rosiglitazone. Patients will have to review statements describing the cardiovascular safety concerns with rosiglitazone.

 

Q7. Why has FDA not removed rosiglitazone from the U.S. market?

 

A: Rosiglitazone can effectively control blood sugar, which prevents short-term complications of diabetes and is a reliable marker for lessening long-term complications.

The data underlying the cardiovascular ischemic risks of rosiglitazone are concerning, but they are not definitive. For those patients who cannot effectively control their blood sugar using alternative medications, the benefits of rosiglitazone may exceed these risks. Using rosiglitazone under these circumstances is a judgment that patients should make with their health care professionals.

In addition, there are also individuals currently taking rosiglitazone who, with full knowledge of the potential risk and in consultation with their healthcare providers, may wish to remain on the drug rather than revise their treatment. FDA's action permits them to do so.

 

Q8: What are international regulators doing about rosiglitazone?

 

A: The European Medicines Agency (EMA) has decided to suspend marketing of rosiglitazone. Patients in Europe will be transitioning to alternative medications, and the drug may be brought back into use if additional information becomes available.

There is substantial agreement between EMA and FDA on the interpretation of the scientific data and the assessment of risks. Both agencies have significant concerns about the risk for cardiovascular ischemia. Each agency is managing this risk of rosiglitazone with what it believes is the best risk management tool it has for this circumstance. Those tools are different and reflect the different regulatory environments in Europe and the United States.

Europe has suspended the product while awaiting additional data to help further clarify the benefit-to-risk profile of rosiglitazone. FDA has markedly restricted patient access to the product and introduced new detailed patient information procedures while it awaits additional information to help further clarify the benefit-to-risk profile of the product.

 

Q9: What additional information on rosiglitazone's safety does FDA hope to obtain?

 

A: FDA is requiring a re-adjudication of the RECORD trial. This was a large randomized study of the cardiovascular safety of rosiglitazone. A re-adjudication is a re-evaluation of the data, ultimately resulting in some conclusion or decision about what the data mean.

 

Q10. FDA is also requiring that the TIDE trial be stopped. What is the TIDE trial and what did it have to do with the safety of rosiglitazone?

 

A: After the July 2007 FDA Advisory Committee meeting on rosiglitazone, FDA, under its new authorities enacted as part of the FDA Amendments Act of 2007, required that the sponsor of rosiglitazone (GlaxoSmithKline) perform a study comparing the cardiovascular safety of rosiglitazone to pioglitazone. The 'Thiazolidinedione Intervention With Vitamin D Evaluation" (TIDE) trial was initiated to meet this requirement.

As part of the September 23, 2010, regulatory action on rosiglitazone, FDA has stopped this trial by placing it on clinical hold. Given the current state of the evidence and FDA's recent actions, for the study to continue, participants would need to be informed of: 

  • the significant concerns that rosiglitazone may cause more cardiovascular disease than pioglitazone—the other thiazolidinedione (TZD) drug available in the United States
  • the restrictions on use of rosiglitazone that will be imposed through the REMS
  • that it is unlikely that, outside the study, the patient would receive rosiglitazone.

According to recent recommendations from an Institute of Medicine committee, such an informed consent process might be justified if the study's outcome could realistically yield a significant benefit to public health. At this point in time, however, FDA does not consider TIDE such a study.

 

Q11: What is FDA doing to better assess the risk of diabetes medications in the future?

 

A: FDA has published a guidance for industry describing what types of data the Agency would like to see in order to evaluate the cardiovascular effects of anti-diabetic therapies. This guidance has new requirements for evaluating the cardiovascular risk of type 2 diabetes drugs.

Please see: Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies toTreat Type 2 Diabetes

 

 

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