FDA Drug Safety Communication: Ongoing Safety Review of GnRH Agonists and possible increased risk of diabetes and certain cardiovascular diseases

For updated information, please see: FDA Drug Safety Communication: Update to Ongoing Safety Review of GnRH Agonists and Notification to Manufacturers of GnRH Agonists to Add New Safety Information to Labeling Regarding Increased Risk of Diabetes and Certain Cardiovascular Diseases

Safety Announcement
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary
Table of Approved Indications for GnRH Agonists in Adults

Safety Announcement

[05-03-2010] The U.S. Food and Drug Administration (FDA) is evaluating whether Gonadotropin-Releasing Hormone (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.

GnRH agonists (sold under the brand names Lupron, Zoladex, Trelstar, Viadur, Vantas, Eligard and Synarel – see Table below) are drugs that lower male hormones, which has the effect of shrinking prostate tumors or slowing the growth of prostate cancer. This therapy is known as Androgen Deprivation Therapy or ADT.

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 agency is reviewing data from published studies comparing outcomes in patients undergoing ADT to treat prostate cancer versus patients not undergoing this treatment.^1-7 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 (see Data Summary below).

At this time, FDA recommends that:

Healthcare professionals should be aware of these potential safety issues and carefully weigh the benefits and risks of GnRH agonists when determining treatment.
Patients receiving GnRH agonists should be monitored for development of diabetes and cardiovascular disease.
Health care professionals should manage cardiovascular risk factors for patients, such as smoking and increases in blood pressure, cholesterol, blood sugar, and weight, according to current clinical practice.
Patients should not stop their treatment with GnRH agonists unless told to do so by their healthcare professional.

These recommendations are consistent with a Science Advisory⁸ 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.

Additional Information for Patients

FDA has not concluded that receiving GnRH agonists increases your risk of diabetes and cardiovascular events. The Agency will continue to review information relating to this safety concern as more information becomes available.
GnRH agonists are sold as the brand names – Lupron, Zoladex, Trelstar, Viadur, and Eligard.
Do not stop your treatment with GnRH agonists unless told to do so by your healthcare professional.
Before receiving GnRH agonists, tell your healthcare professional if you have diabetes, heart disease, a previous heart attack or stroke, or any cardiovascular risk factors like high blood pressure, high cholesterol, or cigarette smoking.
If you have any concerns about receiving these medicines, talk to your healthcare professional.

Additional Information for Healthcare Professionals

FDA has not concluded that GnRH agonists increase the risk of diabetes and cardiovascular events in patients using these medications for prostate cancer.
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.
Follow the recommendations in the drug label when prescribing GnRH agonists.
Carefully weigh the known benefits and risks of GnRH agonists when determining appropriate treatment for prostate cancer.
Monitor patients for diabetes and cardiovascular events in patients receiving GnRH agonists.
Ensure that cardiovascular risk factors such as blood pressure, cholesterol, blood sugar, weight, and smoking are managed according to current clinical practice.

Data Summary

The FDA is reviewing several published observational studies and one controlled randomized clinical trial comparing patients receiving ADT, primarily GnRH agonists, to those receiving other treatments for prostate cancer.^1-7

The observational studies used administrative claims and registry data to compare patients with prostate cancer receiving GnRH agonists to those who received other treatments for prostate cancer. Although most of these studies reported small statistically significant increased risks for diabetes and/or cardiovascular disease with the use of GnRH agonists, there are several study design limitations that make a cause-and-effect relationship difficult to confirm. 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 has not concluded that receiving GnRH agonists increases your risk of diabetes and certain cardiovascular diseases. The Agency will continue to review information relating to this safety concern as more information becomes available.

Table of Approved Indications for GnRH Agonists in Adults

Brand Name	Generic Name	Approved Uses
Lupron	Leuprolide acetate	Palliative treatment of advanced prostatic cancer.
Lupron Depot 3.75 mg	Leuprolide acetate	Management of endometriosis, including pain relief and reduction of endometriotic lesions. Used monthly with norethindrone acetate 5 mg daily for initial management of endometriosis and for management of recurrence of symptoms. Concomitantly with iron therapy is indicated for the preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata (fibroids).
Lupron Depot 22.5 mg	Leuprolide acetate	Palliative treatment of advanced prostatic cancer.
Zoladex 3.6 mg	Goserelin acetate	Palliative treatment of advanced carcinoma of the prostate. In combination with flutamide for the management of locally confined Stage T2b-T4 (Stage B2-C) carcinoma of the prostate. Management of endometriosis, including pain relief and reduction of endometriotic lesions for the duration of therapy. Palliative treatment of advanced breast cancer in pre- and perimenopausal women. Use as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding.
Zoladex 10.8 mg	Goserelin acetate	Palliative treatment of advanced carcinoma of the prostate. In combination with flutamide for the management of locally confined Stage T2b-T4 (Stage B2-C) carcinoma of the prostate.
Trelstar	Triptorelin pamoate	Palliative treatment of advanced prostate cancer.
Viadur	Leuprolide acetate	Palliative treatment of advanced prostate cancer.
Eligard	Leuprolide acetate	Palliative treatment of advanced prostate cancer.
Vantas	Histrelin acetate	Palliative treatment of advanced prostate cancer.
Synarel	Nafarelin acetate	Management of endometriosis, including pain relief and reduction of endometriotic lesions.

*Leuprolide Acetate has generic formulations

References:

1. Keating NL, O'Malley JO, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006;24:4448-4456.

2. Keating NL, O'Malley JO, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of Veterans with prostate cancer. J Natl Cancer Inst 2010;102:39-46.

3. Tsai HK, D'Amico AV, Sadetsky N, Chen M-H, Carroll PR. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 2007;99:1516-1524.

4. Saigal CS, Gore JL, Krupski TL, Hanley J, Schonlau M, Litwin MS, and the Urologic Diseases in America project. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 2007;110:493-500.

5. Van Hemelrijck M, Garmo H, Bratt O, Bill-Axelson A, Lambe M, Stattin P, et al. Increased cardiovascular morbidity and mortality following endocrine treatment for prostate cancer: an analysis in 30,642 men in PCBaSe Sweden. Eur J Cancer Supplements 2009 (September);7(3):1 (abstract 1BA). Joint ECCO 15 - 34^th ESMO Multidisciplinary Congress, Berlin 20-24 September 2009.

6. Alibhai SMH, Duong-Hua M, Sutradhar R, Fleshner NE, Warde P, Cheung AM, et al. Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol 2009;27:3452-3458.

7. Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich MV, Sandler HM, Smith MR. Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31. J Clin Oncol 2008;27:92-99.

8. Levine GN, D'Amico AV, Berger P, Clark PE, Eckel RH, Keating NL, et al on behalf of the American Heart Association Council on Clinical Cardiology and Council on Epidemiology and Prevention, the American Cancer Society, and the American Urological Association. Androgen-deprivation therapy in prostate cancer and cardiovascular risk. A science advisory from the American Heart Asociation, American Cancer Society, and American Urological Association. Circulation 2010;121:831-838.

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