FDA Panel Reviews VTE Risk for Some OCs


From a Meeting of the FDA's Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee

ADELPHI, MD. – The benefits of Yasmin and other drospirenone-containing oral contraceptives outweigh their risks, but more information about the agents' risk-benefit profile needs to be added to the labels, according to the majority of a Food and Drug Administration advisory panel.

The agency convened a joint meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee to review the conflicting results of numerous epidemiologic studies evaluating the risk of venous thromboembolic events (VTEs) associated with Yasmin, Yaz, and other combined oral contraceptives (COCs) that contain drospirenone as the progestin component. Panelists voted 15-11 that the benefits of these products for preventing pregnancy “in the general population of women” outweighed their risks, and voted 21-5 that the labels for these products did not adequately reflect available information about their risk-benefit profile.

In 2001, Yasmin (0.03 mg of ethinyl estradiol with 3 mg of drospirenone) was the first COC that contained drospirenone, a spironolactone analogue, that was approved, followed by Yaz (0.02 mg of ethinyl estradiol with 3 mg of drospirenone) in 2006, and Safyral and Beyaz, folate-containing versions of Yasmin and Yaz, respectively, which were approved in 2010. Some generic formulations are also available.

Postmarketing studies conducted by Bayer HealthCare Pharmaceuticals, the manufacturer of Yasmin, Yaz, Safyral, and Beyaz in Europe and the United States, found no increased risk of VTE compared with other COCs. But other epidemiologic studies, including a recently reported FDA-funded study of more than 800,000 women, have found an increased risk of VTE associated with these products, when compared with standard low-dose COCs. Some of the information about VTE risk has been added to the labels of these products, but panelists recommended providing more information, which would help clinicians counsel patients.

Those who voted that the benefits outweighed the risks – which included the obstetrician-gynecologists on the panel – said that if the risk was elevated, it was modest, and emphasized the importance of having more contraceptive choices available. They pointed out that the absolute risk of VTEs was small, and was less than the risk during pregnancy and the postpartum period.

“I voted yes because I think the elevation in risk, if it exists, is modest and it is outweighed by the risk in pregnancy … and I think having more choices is appropriate,” said Dr. Eve Espy of the department of obstetrics and gynecology, University of New Mexico, Albuquerque.

“I don't think the data are sufficient with the current studies to be able to say that there is a risk,” added the acting chair of the panel, Dr. Julie Johnson, professor and chair of obstetrics and gynecology, University of Massachusetts, Worcester. However, she said that she had significant concerns about the results of the FDA-funded study, adding that she did not think the drospirenone-containing OCs have any advantage over any other OCs, and “if there truly is an increased risk I would vote differently.”

Those who voted that the benefits did not outweigh the risks also cited the lack of any unique benefits of drospirenone-containing COCs over available alternatives, and noted that there were plenty of other choices available for women. “When weighing risks and benefits for patients, I have to see that there's some benefit,” said Dr. Peter Kaboli of the University of Iowa, Iowa City. “So the number needed to treat to have some benefit in this case might even be an infinite number because there is no benefit … and I wouldn't recommend this to my patients and I would not have my daughter take it, so I voted no.”

Also voting no, Dr. Maria Suarez-Almazor, professor in the department of medicine, University of Texas MD Anderson Cancer Center, Houston, said, “there's no clear evidence of benefits over the many other forms of birth control and oral contraceptives.” With respect to the risks, “I was a little disturbed by the fact that every single study that was not funded by industry found an increased risk, and it was only the studies that were funded by industry that showed no risk.”

Dr. Lisa Soule, of the FDA's Division of Reproductive and Urologic Products, said at the meeting that because many factors can influence risk, data need to be reanalyzed to evaluate the impact of these risk factors “before we can conclude that Yasmin carries an increased risk of VTE.” (She referred to Yasmin since that is the most studied of all these products.)

Panelists agreed that all of the studies had strengths and weaknesses, and that the effects of obesity, family history, smoking, and other possible confounding factors on risk in the studies should be further evaluated.


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