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Podcast for Healthcare Professionals: Ongoing Safety Review of GnRH Agonists and possible increased risk of diabetes and certain cardiovascular diseases

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Welcome, my name is Mary Kremzner, a pharmacist in the Division of Drug Information. I am updating you on an ongoing safety review of the class of medications known as Gonadotropin-Releasing Hormone Agonists or GnRH Agonists.

On May 3rd, 2010, FDA announced that the agency is evaluating whether GnRH Agonists may increase the risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke) in men receiving these medications for the treatment of prostate cancer.

FDA's review is ongoing. The agency has not made any conclusions about GnRH agonists and whether they increase the risk of diabetes and cardiovascular disease in patients receiving these medications for prostate cancer.

The FDA is reviewing six published observational studies (using administrative claims and registry data) and one controlled randomized clinical trial comparing patients receiving ADT, primarily GnRH agonists, to those receiving other treatments for prostate cancer. In six of the studies, there was a reported small increased risk of diabetes and/or cardiovascular disease in patients undergoing ADT. However, these studies have design limitations that make it difficult to confirm a cause-and-effect relationship.

The limitations include:

  • Variable definitions of ADT--sometimes aggregated to include GnRH agonists, androgen receptor antagonists, and orchiectomy;
  • Limited information on drug exposure (drug, dose, and schedule);
  • Variable definitions of cardiovascular disease including aggregated outcomes;
  • Lack of inclusion of nonfatal serious outcomes in two studies;
  • Missing data on risk factors for cardiovascular disease, smoking, body mass index, cholesterol, blood pressure, and current medications;
  • No prior testing and exclusion from studies of patients with underlying undiagnosed cardiovascular disease;
  • Possible undetected and misclassified fatal myocardial infarctions and sudden death, and no validation of cardiovascular or diabetes diagnoses; and
  • Possible detection bias due to increased physician contacts for follow-up visits for patients receiving GnRH agonists.

At this time, FDA recommends that Healthcare Professionals

  1. Know that FDA has not concluded that GnRH agonists increase the risk of diabetes and cardiovascular events in patients using these medications for prostate cancer.
  2. Understand that most of the studies reviewed by FDA reported small, but statistically significant increased risks of diabetes and/or cardiovascular events in patients receiving GnRH agonists.
  3. Follow the recommendations in the drug label when prescribing GnRH agonists.
  4. Carefully weigh the known benefits and risks of GnRH agonists when determining appropriate treatment for prostate cancer.
  5. Monitor patients for diabetes and cardiovascular events in patients receiving GnRH agonists.
  6. Ensure that cardiovascular risk factors such as blood pressure, cholesterol, blood sugar, weight, and smoking are managed according to current clinical practice.

These recommendations are consistent with a Science Advisory issued by the American Heart Association, American Cancer Society, and American Urological Association, in the February 2010 issue of the journal, Circulation.

Some GnRH agonists are also used in women for the management of endometriosis, preoperative improvement of anemia caused by uterine fibroids, and palliative treatment of advanced breast cancer. For uses other than breast cancer, the recommended length of treatment with GnRH agonists should not exceed one year. There are no known comparable epidemiologic studies evaluating the risk of diabetes and cardiovascular disease in women taking GnRH agonists.

Some GnRH agonists are also used in children to treat central precocious puberty. There are no studies that have evaluated the risk of diabetes and heart disease in children taking GnRH agonists.

This communication is in keeping with FDA's commitment to inform the public about its ongoing safety review of drugs. The Agency will continue to review information relating to this safety concern as more information becomes available.

Thank you for listening. The FDA is committed to keeping healthcare professionals informed of the latest safety information. If you any have questions about this safety communication, you can reach the Division of Drug Information at the following email address: druginfo@fda.hhs.gov.


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