Dangers of birth control patch come to light.

The Ortho Evra contraceptive patch is marketed as an easier alternative to oral contraceptives. But this convenience comes at a price: a greater risk of side effects, especially blood clots. The patch and the pill contain similar hormones, but studies have revealed that the patch delivers more estrogen and may be more dangerous than the pill.

The only transdermal birth control patch on the market, Ortho Evra delivers hormones through the skin and directly into the bloodstream. More than 60 lawsuits have been filed against the patch's maker, alleging that the patch caused deaths and injuries such as blood clots, heart attacks, and strokes.

Plaintiffs claim that the manufacturer, Ortho McNeil Pharmaceutical, Inc., and its parent company, Johnson & Johnson, misled patients and health care providers about the product's safety. The lawsuits include claims of defective design, failure to warn, breach of warranty, negligence, and wrongful death.

"The various sales messages sent to health care providers failed to warn that the patch carried a higher risk of blood clots than oral contraceptives and actually implied that the patch carried the same risk as a pill," according to a complaint filed in a California trial court earlier this year. (Thoren v. Johnson & Johnson, No. 106CV056536 (Cal., Santa Clava County Super Ct. filed Jan. 20, 2006).)

In November, the FDA issued a warning that the patch exposes users to 60 percent more estrogen than does a typical pill containing 35 micrograms of estrogen. The company changed its label to reflect the warning.

Then, in February, Johnson & Johnson released conflicting findings from two ongoing epidemiological studies it sponsored. One found that the risk of nonfatal venous thromboembolic events (VTE)--blood clots--for women using the patch is similar to that of the pill; an interim report from the other study found twice the risk of VTE with the patch than with the pill. Both studies are still evaluating the risk of heart attack and stroke.

At press time, two cases had been filed as class actions but had not yet been certified, said Lori Andrus, a San Francisco lawyer and chair of ATLA's Ortho Evra Litigation Group. Thirteen cases have been centralized in a multi-district litigation (MDL) and transferred to the Northern District of Ohio. (In re Ortho Evra Prods. Liab. Litig., MDL 1742 (J.P.M.L. Mar. 1, 2006).)

The number of deaths and injuries linked to Ortho Evra is difficult to quantify because the FDA's Adverse Event Reporting System is voluntary said Jason Mark of Great Neck, New York, whose firm has filed more than 20 Ortho Evra cases in federal and state court. The Associated Press reported in November that about a dozen women died in 2004 of blood clots believed to be related to the patch. (Martha Mendoza, Warning Issued for Birth-Control Patch, Associated Press, Nov. 11, 2005.)

"I think it ought to come off the market right away," said Ray Chester, an Austin, Texas, lawyer representing the plaintiff in Thoren and several others in federal and state cases. "I think all Ortho Evra users ought to be advised to discontinue it immediately."

Informing patients

Ortho Evra's manufacturer sent out "dear doctor" letters about the label change, said Julie Keenan, communications director for Ortho Women's Health (part of Ortho McNeil). However, the company did not notify patients directly, so they learned of the warning by reading the revised label, from their health care providers, or through news reports. The company issued a press release in February about the epidemiological studies, Keenan said.

Mark noted that the company's lack of direct communication with patients about the new warning stands in contrast to its "extensive direct-to-consumer advertising."

Chester believes most Ortho Evra users are aware of the warning because many prescribing physicians notified patients using it. But, he added, "there wasn't any formal procedure by the manufacturer or the FDA to notify current users."

Andrus said she does not think the warning reached most users, and even those who learned of the warning might not appreciate its significance.

"Women need to know what the consequences of additional estrogen are," Chester said. The higher estrogen level in the patch "makes it equivalent to a 50-microgram (or more) pill, and those have been virtually outlawed since the 1980s worldwide," in part because of the risk of blood clots. That warning is "not really getting through," he said.

The California State University system and the Pennsylvania State University informed students who had been prescribed Ortho Evra by campus health services about the FDA warning. Margaret Spear, a physician and director of Penn State's health services, said that most students agreed to switch to another form of contraception, but that "after fully informing the patients about the risks and alternatives, we will continue providing prescriptions to some students."

Gregg Lichtenstein, medical director of San Diego State University's health services, noted that its pharmacy has seen a drop in demand for the patch.

Patch versus pill

As the pill is token each day, hormone levels in the body go up and down--in peaks and troughs--but the patch delivers a steady stream of hormones. For this reason, patch users' peak estrogen level is 25 percent lower than that of pill users, although their overall estrogen level is 60 percent higher, according to the FDA warning.

Different types of oral contraceptives provide different doses of estrogen, but the patch comes in only one strength.

"One of the flaws with the transdermal birth control patch is that it's a uniform size and intends to deliver a uniform amount of hormones for every woman," regardless of her body size, Andrus said.

Ortho Evra's label warns that it may be less effective in women who weigh 198 pounds or more. "Some people don't get enough of the hormones and get pregnant, and others get too much of the hormones and get blood clots," Chester said.

In addition to clots, the label describes risks such as heart attacks and strokes, noting that this information "is derived primarily from studies of birth control pills." However; Mark said, "the patch and the pill are two completely different products with completely different pharmacokinetic profiles." Hormones from the patch travel directly through the skin and into the bloodstream, but hormones from the pill first go through the intestines and the liver, getting broken down along the way.

Like oral contraceptives, Ortho Evra contains a combination of estrogen (which is prothrombotic, or causes clotting) and progestin (which is antithrombotic), and the use of both balances clotting potential, Mark explained. The type of progestin in the patch--norelgestromin--may cause a higher risk of clots than other progestins, he said.

The FDA officer reviewing the new drug application for Ortho Evra in 2001 noted that "there remains a definite clinical concern about the possibility of an increased risk of VTE events with Evra, containing norelgestromin, an NME [new molecular entity]...."

The company tested Ortho Evra on 3,300 women before it was approved. In these studies, two users had pulmonary emboli. That number was not considered statistically significant, but those two cases represent "at least six times the clotting rate historically attributed to a widely used class of oral contraceptives using the hormone levonorgestrel," the Thoren complaint alleges.

The FDA officer also noted: "Post-marketing surveillance for DVT [deep vein thrombosis] and PE [pulmonary embolus] events will be important, as these are potential serious adverse risks (with two cases of pulmonary emboli in the clinical trials) with this new delivery system for contraception...."

Plaintiffs say Ortho McNeil has failed to conduct any meaningful surveillance. The issue of what exactly the company has done is a big question in the litigation, Mark said.

The family of Kathleen Thoren, who suffered a stroke and died after using Ortho Evra for less than a month, alleges that the defendants knew about the increased risks long before she began using the patch in November 2004. The plaintiffs allege that the company "withheld or misrepresented or failed to properly submit required material information to the FDA concerning the patch before and after approval." The complaint also says the November 2005 label change was based on information the defendants had known since the summer of 2003.

Mark noted that some preapproval testing "appears to be very, very minimal, focusing more on efficacy rather than safety."

Chester said he does not find fault with the manufacturer's testing methods or the information it gathered, but rather with "what they did about the warning signal they got out of it--which was nothing."

The November 11 Associated Press report said that in an internal Ortho McNeil memo, the company refused to fund a study comparing Ortho Evra and its Ortho-Cyclen pill in 2003 because of concerns there was "too high a chance that study may not produce a positive result for Evra."

Mark represents Marilyn Rose Wilson, who suffered bilateral pulmonary emboli after using the patch. She sued the company, alleging that Ortho Evra was insufficiently tested and that "the defendants' intentional and/or reckless failure to disclose information deprived [the] plaintiff of necessary information to enable her to weigh the true risks of using the subject product against its benefits." (Wilson v. Johnson & Johnson, No. 2:06-cv-00794-KSH-PS (D.N.J. filed Feb. 22, 2006).)

Many factors may contribute to the higher levels of estrogen women are exposed to through the patch, Mark said. One is the patch's location on the body. He noted that one study indicated "a patch on the abdomen will give 20 percent less exposure than one on another area of the body, like the arm, torso, or buttock."

Heat is another factor. The Philadelphia Inquirer reported on March 5 that the FDA was launching an "exhaustive review" of medical patches' safety and how heat affects them.

On March 7, Ortho McNeil issued a warning that heat may increase absorption of the pain medication Duragesic (fentanyl) in another transdermal patch it makes. Increased temperature from heating pads, electric blankets, sunbathing, and hot baths, for example, "could cause you to receive more medication than you should from the patch," the warning says. Millions of Duragesic patches were recalled in 2004. (See Rebecca Porter, Medical Patch Users Discover Danger Beneath the Surface, TRIAL, Feb. 2005, at 16.) Last year, the FDA announced it was investigating 120 deaths linked to fentanyl.

Progress of litigation

Chester noted that his Ortho Evra cases in state court generally have progressed further than the federal cases. Some have been settled, and "a lot of discovery has been done," he said. The first trial is set for February 2007.

Centralization of multidistrict litigation will help both plaintiffs and defendants understand early in the litigation the value of the claims and the dispositive legal issues, Andrus said. She noted that that in other recent MDLs involving pharmaceutical products and medical devices--such as Guidant and Medtronic implantable defibrillators and the drugs Bextra, Celebrex, and Vioxx--"the federal judges have been pushing the cases along at a fast clip in terms of discovery but have also been scheduling and carrying out early, bellwether trials."

She added that this development seems "very different from what we've seen in the past few years, which can sometimes be a very thorough and methodical trudge through the discovery process for years and years."

Mark said the Ortho Evra litigation will explore whether Ortho McNeil could have used different designs and manufacturing processes to make the patch safer. He noted that the Canadian version of the product is manufactured differently than the U.S. version and contains a smaller dose of hormones.

"It just doesn't make sense for this product to exist," Chester said. "There's no need for it that justifies the additional risk. No warning will solve that fundamental risk-benefitimbalance."