Bayer HealthCare Pharmaceuticals' combined oral contraceptive Yaz (drospirenone/ethinyl estradiol) and Johnson & Johnson's combination contraceptive patch Ortho Evra (ethinyl estradiol/norelgestromin transdermal system) appear to be leading their class in updated label warnings about the risk of venous thromboembolism.

But Bayer's oral contraceptive franchise could be facing further labeling changes in light of new epidemiological studies showing a two- to three-fold increased risk of blood clots with drospirenone, a third-generation contraceptive, compared with a second-generation agent levonorgestrel.

In addition to Yaz, Bayer's oral contraceptive products Yasmin, Safyral and Beyaz also contain drospirenone. In a press release, Bayer said it stood behind the safety of its drospirenone-containing contraceptives and challenged the methods and databases used in the new studies, which were published April 21 in the British Medical Journal.

More Specifics On Timing Of VTE Risk

FDA approved the Yaz label update March 11. New language in the "Thromboembolic Disorders and Other Vascular Problems" subsection of the "Warnings and Precautions" section provides more specific information about the timing of VTE risk than was previously included.

"The risk of VTE is highest during the first year of use," the revised Yaz label states. "Interim data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first six months of COC use. Interim data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a four-week or greater pill-free interval) the same or a different COC."

The Ortho Evra label change FDA approved March 23 elevates the VTE risk from the "Warnings" section to the boxed warning already present on the label. Information on the pharmacokinetic profile of ethinyl estradiol was moved from the clinical pharmacology section into the boxed warning. In addition, language already in the boxed warning about the elevated risk of serious cardiovascular events for cigarette smokers was modified to be consistent with labeling for combination hormonal contraceptives, and the box itself was moved to the beginning of the label.

"These recent changes to the Ortho Evra label are not linked to any recent changes to Bayer's label," J&J said in an email. "Additionally, there are no new data regarding these previously described risks."

FDA declined to discuss whether revised VTE warnings are planned for other combination contraceptives although it stands to reason that labeling changes are in store for other products. Bayer Vice President of Medical Affairs Leo Plouffe said in an interview the company is working with FDA to extend the revised warnings to all of the firm's contraceptives in the U.S.

Data Coming In From Long-Term Studies

The new warning for Yaz springs from "large-scale post-marketing studies we commissioned to examine the cardiovascular risks of not only our own combination oral contraceptives ... but also other prescribed COCs," Bayer said in a statement.

The study, called the Long-Term Active Surveillance Study for Oral Contraceptives (LASS), is a multinational, prospective cohort, five-year follow-up safety study to the European Active Surveillance (EURAS) study, with cardiovascular events, including VTE, being the main clinical outcomes.

According to ClinicalTrials.gov, LASS is studying three groups of women: those taking contraceptives containing drospirenone, levonorgestrel or other progestogens. The study is expected to be complete in December. The Yaz label change was based on interim data.

"This latest language update on Yaz is really a class effect for oral contraceptives from our data, which are reflective of a range of COCs included in the EURAS and LASS trials," Plouffe said.

"What we have now is more clarity in the timing of events. VTE was known as a risk, then it was known as a risk within the first year, now it's known as a risk within the first six months. And in all that data, it wasn't clear if switching from one COC to another or stopping increased the risk. Now we know if that if you switch or stop for less than four weeks, there is no increased risk, but if you stop for more than four weeks, there is an increased risk when you start again."

BMJ Studies Contrast With Bayer's Findings

The labels for Bayer's drospirenone-containing contraceptives reflect the results of EURAS and a second prospective cohort study, Ingenix, which similarly showed a comparable risk of thromboembolism compared to use of other COCs, including those containing levonorgestrel. However, two studies recently published in the BMJ contradict those findings.

The two case-controlled studies looked at the risk of non-fatal VTE in women using drospirenone-containing oral contraceptives compared with those taking levonorgestrel. One study used U.S. medical claims data, while the second used data from the U.K. General Practice Research Database.

The U.S. study found an approximate doubling in the risk of nonfatal VTE with drospirenone compared with levonorgestrel, while the U.K. study reported a three-fold increased risk.

In both studies the overall VTE risk remained low. Incidence rates in the U.S. study were 30.8 and 12.5 per 100,000 woman years among drospirenone and levonorgestrel users, respectively. The U.S. study authors, Susan Jick, Boston University, et al., say the findings support other epidemiological studies suggesting drospirenone confers a heightened VTE risk over levonorgestrel and "in the absence of other considerations should not be the first choice in oral contraception."

When asked whether the new epidemiological data would be added to the labels of Bayer's drospirenone-containing products, FDA said it is currently reviewing the BMJ publications.

In a press release, Bayer said its review of the BMJ studies suggests "that the manner in which the authors applied the study methodology ... and the databases used provide less reliable conclusions than are available from existing scientific evidence around the risk of developing" VTEs with COCs.

"Given the already large and robust scientific body of evidence, in Bayer's opinion, these studies do not change the overall assessment about the safety of Bayer's oral contraceptives," the company said. "Bayer's assessment that its drospirenone-containing COCs are safe and effective when taken as directed according to prescribing information is supported by consistent clinical findings over a 15-year period and up to 10 years of post-marketing study results which support that the risk of VTE is similar with any COC studied, regardless of the progestin," Plouffe said in the press release.

Bayer told "The Pink Sheet" DAILY the company would work closely with FDA in evaluating the relevance of the two studies.

- Martin Berman-Gorvine (m.berman-gorvine@elsevier.com), Sue Sutter (s.sutter@elsevier.com)

Bayer's Yaz May Face More Labeling Changes On Blood Clot Warnings

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