• The EVRA product monograph now includes new information on the average daily release rates of the contraceptive hormones norelgestromin (200 micrograms  every 24 hours) and ethinyl estradiol (35 micrograms every 24 hours). This information replaces the previously labeled daily delivery rate of norelgestromin (150 micrograms every 24 hours) and ethinyl estradiol (20 micrograms every 24 hours).
• The new information on the average daily release rate was determined by measuring hormone content that remained in the EVRA patches worn by women for 7 days. The previously labeled delivery rate information was estimated using a different method. The term "release rate" has replaced the previously labeled term "delivery rate" as a more descriptive term regarding release of hormones from the patch.
• There has been no change to the way the EVRA patch is made. The estimates of actual exposure to the hormones from the EVRA patch (amount of contraceptive hormones actually measured in the blood stream) have not changed. There is no known impact on the safety and effectiveness of the EVRA patch as a result of the new information on the average daily release rate.

When Ortho Evra was introduced in 2002, Johnson & Johnson touted the once-weekly patch as a convenient alternative to daily oral contraceptive pills. The drug's original safety label stated that the patch's health risks were similar to those related to oral contraceptives. But in 2005, the FDA warned that women using Ortho Evra were exposed to approximately 60% more estrogen than those who used oral contraceptive pills. High levels of estrogen can greatly increase the risk of developing blood clots, heart attacks, strokes and other serious injuries. As of November 2005, the FDA had received twenty-one reports of life-threatening blood clots and other ailments associated with the use of Ortho Evra. Then a study was published that showed women using Ortho Evra were twice as likely to suffer blood clots as those taking oral birth control pills. That study prompted the FDA to request a change on the Ortho Evra label to include a stronger safety warning.

According to Bloomberg.com, the Ohio filing offers the first detailed look at evidence previously deemed confidential by the judge and may indicate why Johnson &Johnson settled dozens of Ortho Evra cases without allowing any to go to trial.   The court papers, which where filed on November 20 in federal court in Toledo, Ohio allege that Johnson & Johnson ``withheld and altered data from the clinical trials which proved that the patch delivered significantly higher levels'' of estrogen than oral contraceptives.  "Obviously unaware of the withheld information, the FDA approved Ortho Evra for marketing.''

The Ortho Evra filing details two Ortho Evra studies conducted by Johnson & Johnson.   The first, conducted in 1999, was called PHI-014. It measured the amount of ethinyl estradiol, or EE as the estrogen component is called, released into the bloodstream every 24 hours. The company said the study proved the level was 20 micrograms.  The actual results showed the patch released 30.4 micrograms when applied to the abdomen and 38.1 micrograms when applied to the buttocks, according to the motion. Johnson & Johnson applied a ``60% correction factor'' to lower the results, the motion said.   The Ortho Evra plaintiffs allege that ``Not only was FDA unaware of the use of the 60% correction factor, but even key company employees profess to know nothing about it.''  Johnson & Johnson also left mention of the correction factor out of a journal article published in 2002, leaving doctors in the dark about the true estrogen exposure face by Ortho Evra Birth Control Patch users.

The second study, known as PHI-017, measured the concentration of estrogen from the Ortho Evra patch compared with three forms of the birth control pill, the motion said. The results showed the patch delivered two times more estrogen than one pill and three times more than the other pills.  According to the November 20 court filing, ``Over the ensuing six years and to the present date, defendants have never mentioned to the FDA the results of PHI- 017,''.   The court papers assert that Johnson & Johnson's failure to provide the FDA with the results of PHI-017 ``was no accident, but instead a very deliberate plan intended to deceive regulators about the high levels of EE delivered by the patch.''

The numbers keep adding up for the Ortho Evra birth-control patch.

Not sales -- those are down sharply -- but the docket of product liability cases filed against Johnson & Johnson, the maker of the one-of-a-kind contraceptive.

In its latest update last month, J&J said more than 2,400 Ortho Evra lawsuits are queued up in state and federal courts. Some 400 are New Jersey cases that have been consolidated in the Middlesex County Courthouse in New Brunswick, just a few blocks from the health-care conglomerate's headquarters.

Most of the lawsuits have a common theme: J&J allegedly knew the skin patch had greater safety risks than birth-control pills, particularly in the incidence of harmful blood clots that could develop in women's legs and lungs. But it chose to aggressively market the contraceptive in ads featuring supermodel Naomi Campbell and others, and soft-pedaled the dangers.

J&J denies the claims, and says Ortho Evra is a "safe and needed" contraceptive if used according to its label.

But the company's defense has a complication: Two former executives have said they raised red flags about the patch's safety but were ignored.

One is Joel Lippman, a medical officer whose claims about problems with Ortho Evra and other products were first made public in a state whistleblower suit last year. The other is a J&J vice president who decided to resign from a job overseeing the "benefit risk and safety evaluation" of reproductive products -- including the patch -- after being unable to properly "exercise this responsibility," according to a recently unsealed document in the New Jersey litigation.

The latter filing is an October 2005 letter addressed to J&J Chief Executive William Weldon by the executive, whose name and exact job title were redacted by the court. The officer said he or she had left the company the previous month in part because Ortho Evra's risks had been downplayed, despite "compelling evidence" to the contrary.

"My discomfort on the issues mentioned above was and is still shared by many of my former colleagues, and several of them asked me to be more open on the reasons for my resignation," the person wrote.

J&J said the former employee, who tracked adverse reactions to the patch after it was on the market, vouched for its safety to both the company and the Food and Drug Administration while working there.

More than 4 million women used Ortho Evra after it was approved for sale in the United States in 2001. It's biggest selling point is convenience -- slap the patch on for a week, and you're set. But having a hormonal contraceptive delivered through the skin turns out to be a different proposition than digesting it in a daily pill.

In 2005, the FDA and J&J agreed to make a change in Ortho Evra's label that said users of the patch could be exposed to 60 percent more estrogen than women who used the pill.

Oral contraceptives have been linked to some risk of harmful side effects, such as deep-vein thrombosis or pulmonary embolism, a potentially fatal condition in which clots form in the body and make their way to the lungs. To the women suing J&J, greater estrogen exposure from the patch means greater risk of death or injury.

"They should have warned about that, and they didn't," said Andres Alonso, a partner with Parker & Waichman, which represents more than 600 Ortho Evra plaintiffs.

Another plaintiff attorney, Gary Douglas, said Johnson & Johnson had data showing the different rates of exposure before the drug was approved. Douglas is scheduled to try the first Ortho Evra case, a wrongful death suit brought by the estate of 18-year-old college student Zakiya Kennedy, this fall in New York.

"Johnson & Johnson not only knew their product delivered more estrogen than the pill, but deliberately manipulated the numbers and results of the clinical trials to reflect that it delivered the same amount as the pill," Douglas said.

Lippman has already been deposed in the New Jersey litigation, according to his lawyer. The executive, who helped oversee clinical trials for the patch, said he raised questions about the "dangerously high levels of estrogen" emitted by Ortho Evra in the late 1990s but was ignored. J&J has said Lippman's allegations are untrue, and that he was fired from another post in 2006 for conduct unrelated to his safety claims.

An FDA medical reviewer cited the potential for clot-related problems with Ortho Evra in 2001, and said post-market studies would be necessary. But the patch was ultimately approved by the agency, and the revised label says "it is not known" if the patch's different profile of estrogen exposure leads to more serious health problems than the pill.

Preliminary data from two, large J&J-funded studies last year were a mixed bag. One showed a twofold increase in events involving clots with Ortho Evra users compared with women who took oral contraceptives. Another showed no difference at all.

Both epidemiological studies are ongoing, and the full results could be critical to the outcome of the litigation.

No trial date is set yet for the New Jersey cases, but jury selection for the Kennedy case is expected to commence on Nov 19. The first federal suit is expected to go on trial in June next year in Cincinnati, Ohio, where U.S. District Court cases have been pooled.

The vice president who wrote Weldon said the company chose to publicize early study data that showed comparable safety results between the patch and the pill, even though J&J was aware of more than 20 deaths that had been tied to Ortho Evra after it hit the market.

"It was decided to quickly try to communicate in priority on these partial and incomplete results, despite compelling evidence that the estrogenic exposure was unusually high compared to an oral product, and that the reporting rate of fatalities and of various thromoboembloic disorders was out of range for this class of products," the executive wrote in the letter.

Weldon did not respond to the executive, but the head of the former employee's business unit arranged a meeting to discuss the concerns soon afterwards, said Gloria Vanderham, a spokeswoman for Ortho Women's Health & Urology, the J&J unit that sells the birth-control patch.

Saddled with inconclusive results from studies, doctors are prescribing other contraceptives. Peak sales of Ortho Evra were $416 million in 2005, but fell 45 percent last year and were off another 39 percent in the first six months of this year, according to IMS Health. In the past year, the patch has been eclipsed by Organon's NuvaRing and an uptick in oral contraceptives.

Still, Wall Street hasn't taken much notice of the Ortho Evra litigation yet. Investors have bigger concerns about J&J, such as the coming patent expirations of several major drugs and the slump in sales of drug-coated coronary stents, said Les Funtleyder, a health-care analyst with Miller Tabak.

"It's sort of on the radar screen, but it's way, way down," Funtleyder said.

On July 8, 2003, the decedent experienced difficulty breathing and collapsed in her home. Paramedics arrived and found the woman in acute respiratory distress. She was taken to the emergency room at St. John Macomb Hospital in Michigan, where emergency room doctors noted she was cyanotic (blue lips and skin) and in severe respiratory distress. The decedent did not respond to CPR and other life-saving measures and was pronounced dead that evening. An autopsy revealed the cause of death as an acute pulmonary embolism.

On November 10, 2005, Ortho McNeil, in conjunction with the FDA, issued a warning about the increased risks of blood clots associated with Ortho Evra. In the new warning, Ortho-McNeil admitted for the first time that women who use the patch will be exposed to up to 60% more estrogen than they would be exposed to if they were taking a birth control pill with 35 micrograms of estrogen. The patch is only intended to deliver 20 micrograms of estrogen. The FDA's announcement on this warning can be found at www.fda.gov/bbs/topics/news/2005/NEW01262.html . It is widely understood that increased exposure to estrogen greatly increases the risk of blood clots, which can cause serious injury or death.

Pulmonary embolism is a sudden blockage in a lung artery, usually due to a blood clot that traveled to the lung from the leg, but clots can also form in the pelvic vein. Pulmonary thromboembolism can be fatal or may result in pulmonary arterial obstruction, pulmonary obstruction, pulmonary infarction, chronic pulmonary hypertension, dyspenea and tachypnea. Symptoms may include shortness of breath, difficulty breathing, anxiety, chest pain, fainting and convulsions. Treatment may include long term use of anticoagulant medications and/or surgery. Recent reports have indicated that the risk of developing blood clots, pulmonary thromboembolism, heart attack and stroke may be significantly higher with the Ortho Evra patch than with oral contraceptive use.

It is alleged that Ortho-McNeil was aware of the increased medical risks associated with Ortho Evra before the drug was approved and that, once approved, the company failed to adequately warn patients about these risks. Evidence shows that the risk of blood clots, heart attack and stroke associated with Ortho Evra is significantly higher than with oral contraceptive pills. The incidence of embolisms and thrombotic injuries in Phase III trials of Ortho Evra was reportedly six times greater than the incidence of such events in oral contraceptives using the hormone levonorgestrel. The FDA has logged 9,116 reports of adverse reactions to the patch in a 17-month period, whereas Ortho Tri-Cyclen, a birth control pill, only generated 1,237 adverse reports in a six-year period. During a 12-month period, 44 serious injuries or deaths have been associated with Ortho Evra, whereas only 17 such reports were linked to the birth control pill during a similar time period. The pattern is further magnified when usage rates are considered: Ortho Tri-Cyclen has six times the number of users as Ortho Evra.

Ortho Evra is an adhesive, transdermal birth control patch that users are instructed to apply to their upper torso, upper outer arm, buttock or abdomen. The patch is intended to release 150 mcg of norelgestromin and 20 mcg of ethinyl estradiol into the bloodstream per 24 hours. It is replaced once a week for three weeks, and no patch is worn during the fourth week during menstruation. The regimen is then repeated. Ortho Evra was approved by the FDA in November 2001, and over 4 million women have used Ortho Evra since its approval. Ortho Evra continues to be marketed aggressively to both consumers and physicians.

About Parker & Waichman, LLP

Parker & Waichman, LLP is a leading products liability and personal injury law firm that represents plaintiffs nationwide. The firm has offices in New York and New Jersey. Parker & Waichman, LLP has assisted thousands of clients in receiving fair compensation for injuries resulting from defective medications and medical devices. The firm is currently representing individuals injured by Vioxx, Bextra, Zyprexa, Ketek, ReNu with MoistureLoc, Guidant Defibrillators and many other defective drugs and medical products. For more information on Parker & Waichman, LLP please visit: www.yourlawyer.com or call (800) LAW-INFO.

More information on this and other class actions can be found on the Class Action Newsline at www.primezone.com/ca

CONTACT:  Parker & Waichman, LLP
          Jason Mark, Esq.
          Melanie H. Muhlstock, Esq.
          (800) LAW-INFO
          (800) 529-4636, Toll-free
          info@yourlawyer.com
          www.yourlawyer.com

In November 2005, after years of debate over the safety of the Ortho Evra birth-control patch, the drug’s manufacturer Ortho-McNeil (a subsidiary of Johnson & Johnson the world’s 4th largest drugmaker) finally acknowledged the fact that women who use the product are at a significantly greater risk of blood clots, stroke, and death than woman who use other forms of oral contraceptives.

Ortho-McNeil has now admitted that women who use the patch can be exposed to up to 60% more estrogen than they would be exposed to if they were taking a birth control pill instead.

Critics of both the ‘patch’ and the FDA’s approval and monitoring practices, however, see the warning as simply another example of economics being placed above public safety. There has been a constant chorus of warnings about the extremely serious side-effects associated with the patch from a number of experts as well as the consumer watchdog group, Public Citizen (www.worstpills.org) and the Associated Press.

Several other lawsuits have already been commenced around the U.S. alleging that serious injuries and deaths have been caused by the Patch.

CBS News also presented a significant story from Austin, Texas, concerning documents produced in the course of a pending lawsuit involving a young mother who was paralyzed by a stroke only 12 days after she began using the patch. She is now a total invalid.        

According to that story, Ortho-McNeil’s own records show the company received some 500 reports of serious health problems associated with the patch between April 2002 and December 2004. During that time only 61 such reports were received with respect to all types of existing oral contraceptives.

In addition, there were four times as many strokes in women using the patch as in women using oral contraceptives even though three times as many women were taking those other forms of birth control.

Finally, the evidence indicated, that in medically confirmed cases, the risk of blood clots is 14 times as high with the patch.   

An investigative report published by the Associated Press on July 18, 2005 linked the birth control patch, which contains a combination of norelgestromin and ethinyl estradiol, to an increased risk of blood clots and deaths (compared to older contraceptives) in some young healthy women.

Ortho Evra, like the other hormonal contraceptives, has a black box warning about an increased risk of cardiovascular adverse reactions in older women who smoke. This type of warning is the strongest that the FDA can request.

The Associated Press follow-up story is even more damning, however. In that article, the AP stated:

“Documents released to attorneys as a result of that litigation show Ortho McNeil has been analyzing the FDA's death and injury reports, creating its own charts that document a higher rate of blood clots and deaths in association with the patch than with the pill.

In addition, an internal Ortho McNeil memo shows that the company refused, in 2003, to fund a study comparing its Ortho Evra patch to its Ortho-Cyclen pill because of concerns there was ‘too high a chance that study may not produce a positive result for Evra’ and there was a ‘risk that Ortho Evra may be the same or worse than Ortho-Cyclen.’”

The patch, like many oral contraceptives, contains two hormones, a progestin and an estrogen. The progestin in Ortho Evra is a new drug (2001) known as norelgestromin, and the estrogen is an existing one known as ethinyl estradiol.

Ortho Evra was approved by the Food and Drug Administration (FDA) in November 2001 and is the first contraceptive product to be approved as a skin patch. It was launched and marketed in a series of “glitzy” television ads featuring “sexy models.” (CBS 11/2/05).
In 2004, the drug accounted for more than 9.9 million prescriptions with sales topping $411 million.

Contraceptives are often referred to as second- or third-generation based on their progestin component. Since some experts classify norelgestromin as a third-generation progestin, Ortho Evra is considered third-generation contraceptive.

Public citizen first listed some third-generation oral contraceptives as “DO NOT USE” drugs in 1998 and 1999 because of an increased risk of blood clots compared to the older, second-generation birth control pills.  Thus, elevated blood levels of progestin as well as estrogen are possible with the Patch.

The Associated Press used the Freedom of Information Act (FOIA) to obtain adverse drug reaction reports for Ortho Evra from the FDA and reportedly found that of the 23 cases in which death was the outcome, doctors reviewing the cases found 17 that appeared to be blood-clot-related, including 12 from 2004.

Since the FDA estimates that it receives reports of only between 1% and 10% of the serious adverse drug reactions that actually occur, the death rate for Ortho Evra may be significantly higher.

The Associated Press also analyzed the reviews of clinical trial results done by FDA physicians and scientists prior to the drug’s approval. Those results were submitted for review by Ortho-McNeil in support of Ortho-Evra and are available on the FDA’s Web site at:

http://www.fda.gov/cder/foi/nda/2001/021-180_ORTHO.htm.

Significantly, Ortho-McNeil and the FDA medical officer reviewing Ortho Evra strongly disagreed about whether two cases of blood clots in the lungs (pulmonary embolus) in young women participating in the pre-approval clinical trials were caused by the drug. The FDA medical officer wrote:

“THE REVIEWER DOES NOT AGREE WITH THE SPONSOR’S [Ortho-McNeil] ABOVE CONCLUSIONS. The two cases of pulmonary embolus, a serious and potentially fatal condition, must be counted as two cases in the group” [emphasis in the original].
The FDA medical officer also included the following statement in his comments:

The professional product labeling and information written specifically for women using Ortho-Evra “should reflect the possible increased risk of venous thromboembolism (VTE) [blood clots] associated with this new transdermal combination hormonal contraceptive containing the new molecular entity progestin norelgestromin (17d-norgestimate).”

In addition, the medical officer expressed concern that 211 out of 3,088 women (6.8%) in the pre-approval clinical trials gained 10 or more pounds in the trials and noted that the contraceptive effectiveness of Ortho-Evra was reduced in women weighing more than 198 pounds (90 kilograms).

The professional product label warns that Ortho-Evra should not be used in the following circumstances:  

• A history of heart attack or stroke
  
• Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
  
• A history of blood clots in the deep veins of your legs
  
• Chest pain (angina pectoris)
  
• Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina
  
• Unexplained vaginal bleeding (until your doctor reaches a diagnosis)
  
• Hepatitis or yellowing of the whites of your eyes or of the skin (jaundice) during pregnancy or during previous use of hormonal contraceptives such as ORTHO EVRA, NORPLANT [levonorgestrel], or the birth control pill
  
• Liver tumor (benign or cancerous)
  
• Known or suspected pregnancy
  
• Severe high blood pressure
  
• Diabetes with complications of the kidneys, eyes, nerves, or blood vessels
  
• Headaches with neurological symptoms
  
• Use of oral contraceptives (birth control pills)
  
• Disease of heart valves with complications
• Need for a prolonged period of bed rest following major surgery
  
• An allergic reaction to any of the components of Ortho Evra

Women who may be using Ortho Evra should contact their physician if any of the following warning signals develop:

• Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung)
  
• Pain in the calf (indicating a possible clot in the leg)
  
• Crushing chest pain or tightness in the chest (indicating a possible heart attack)
  
• Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke)
  
• Sudden partial or complete loss of vision (indicating a possible clot in the eye)
  
• Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your doctor or health care professional to show you how to examine your breasts)
  
• Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor)
  
• Severe problems with sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression)
• Jaundice or a yellowing of the skin or eyeballs accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light  colored bowel movements (indicating possible liver problems)

Since contraceptives are usually prescribed to young, healthy women they should be associated with the lowest possible risk of serious adverse drug reactions.

Blood clots in the lungs were seen in two women given Ortho Evra in clinical trials conducted before the drug was even approved (in addition to several similar cases after the drug was marketed).

There is also no evidence that the patch is a superior contraceptive compared to older second-generation birth control pills.  As stated in the September 2005 issue of Worst Pills Best Pills (published by Public Citizen); “Rarely do randomized pre-approval studies, the scientific ‘gold standard’ for proving safety or efficacy, present such strong evidence of a serious problem.”  

As a result of what it considers strong evidence of the increased risk of blood clots and death, Public Citizen states: “There is no medical reason for women to use the more dangerous Ortho Evra rather than one of the older, better understood, and equally effective oral contraceptives.”

When reading the November 2005 Ortho-McNeil’s Press Release, the first thing that becomes obvious is that the company made a concerted effort to present the information in a way that was difficult (if not impossible) for anyone but an expert to understand.

For example, the acronym AUC is used without definition thereby making the references to estrogen concentrations difficult to extrapolate. AUC, however, is a measure of how much of a drug reaches the bloodstream in a set period of time, usually 24 hours. AUC is calculated by plotting drug blood concentration at various times during a 24-hour or longer period and then measuring the area under the curve between 0 and 24 hours.

When the implications of AUC are considered with respect to the amount of estrogen that can be released in a given period of time, the result is shocking since that amount can easily exceed 50 mg which is well beyond the level already determined to be unsafe.
A previous study conducted with respect to another contraceptive product (the “vaginal ring”) documented these excessively high levels of estrogen associated with the patch almost a year ago in the journal Contraception.

In addition to the risks already discussed cigarette smoking increases the risk of serious cardiovascular side effects from hormonal contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. As a result, women who use hormonal contraceptives, including Ortho Evra, should not smoke.

Finally, litigation involving Ortho Evra has been gaining momentum in recent months and especially in light of the Associated Press investigation. The litigation focuses on the claim that Ortho-McNeil knew of the blood clot risk and even disagreed with the FDA medical officer who suspected the two incidents that occurred during the clinical trial were related to the drug.

A lawsuit was filed in July 2005 against Ortho-McNeil on behalf of a 30-year-old woman who suffered fatal blood clots thought to be linked to the Ortho Evra risk. The woman was admitted into the intensive care unit shortly before her death suffering from severe headache, visual problems, vomiting, and nausea.

The other deaths reported in connection with Ortho Evra risk factors were the result of heart attacks and strokes. One of the most recent deaths linked to Ortho Evra was suffered by a 25-year- old woman who suffered fatal headaches thought to be linked to a surge of hormone release from the birth control patch.

The youngest woman to die (as reported to that point) was an 18-year-old college student who collapsed in the New York subway. As of February ten other women ranging in age from 18 to 27 had also sued Ortho-McNeil.

In September 2005, Parker & Waichman announced it had filed suit against Ortho-McNeil on behalf of a 37-year-old woman who suffered a pulmonary embolism after using the Ortho Evra contraceptive patch for seven months. That suit was also filed U.S. District Court for the District of New Jersey.

According to the complaint in that lawsuit, from April 2002 through September 2003, the U.S. Food and Drug Administration logged 9,116 reports of adverse events because of the patch.

This is significant since there were only 1,237 adverse reports by women taking the leading oral contraceptive, Ortho Tri-Cyclen, over a six-year period even though that drug was used by almost six times as many women as Ortho Evra in 2003.
Ortho-McNeil has routinely denied the allegations that these deaths and injuries were the result of Ortho Evra risk factors. It claimed that the “unsolicited reports” it received were not reliable evidence of a problem with the drug.

The company also claimed its own investigation had not found any causal factor linking these deaths to Ortho Evra and relied on the absence of any reports of fatal adverse side-effects during the clinical trials as proof of the drug’s safety.

Ortho-McNeil’s reluctance to accept even the possibility that the patch could be at fault has lead to the drug being kept on the market without adequate warnings. Even the company’s press release and FDA advisory regarding new labeling requirements do not satisfy the patch’s many critics.

In the eyes of those critics, the fact that Ortho-McNeil notified the FDA that it has undertaken a “much larger study” with respect to the potential problem of blood clots, strokes, and death associated with the patch merely prolongs the time in which millions of women are exposed to an unacceptable risk of catastrophic injuries and death.

In addition to the rather cryptic press release issued by Ortho-McNeil in November 2005 concerning the serious risks associated with its Ortho Evra birth control patch, the FDA published its own information for consumers wishing to learn more about those potentially fatal side-effects (http://www.fda.gov/bbs/topics/news/2005/NEW01262.html) as well as a series of questions and answers. (http://www.fda.gov/cder/drug/infopage/orthoevra/qa.htm)

Some of the more telling remarks in the FDA material follow:

“FDA is announcing a revision to the label for the drug Ortho Evra. This change includes a new bolded warning about higher exposure to estrogen. Higher levels of estrogen may put some women at increased risk for getting blood clots.”

“A woman on Ortho Evra may be exposed to approximately 60% more estrogen than if she were taking a typical 35 microgram estrogen birth control pill. Estrogen use is linked to blood clots in the legs and lungs and other clotting problems such as strokes and heart attacks.”

“In general, woman may be at higher risk for getting side effects if she takes higher doses of estrogen. Women should discuss with their health care professional whether the Ortho Evra patch is a good method of contraception for them.”

Following the November 2005 Ortho-McNeil Press Release and FDA Advisory, there have been several reports of doctors and other healthcare providers curtailing or even suspending the prescribing of the patch.

The Wall Street Journal (WSJ)  reported that: “Many doctors have stopped writing prescriptions for a popular form of birth control after the Food and Drug Administration warned earlier this month of increased hormone exposure to women who use it.”

(http://online.wsj.com/article/0,,SB113262165542103693,00.html?mod=djemHL).

According to the WSJ:  “[A] number of individual practitioners and major health-care providers say they don't want to take any chances. In Memphis, Tenn., obstetrician and gynecologist Henry Sullivant says he has stopped writing new patch prescriptions and suggests that his roughly two dozen patch users try other forms of prescription contraceptives, such as the pill or a monthly vaginal ring. Pennsylvania State University, which provides health services for 42,000 students, is no longer issuing prescriptions and says it is considering whether to contact all students who have been given prescriptions for Ortho Evra, even if they are no longer at the university.”

In a effort to exercise caution, similar actions are being taken by many other university health officials including those at the University of Texas at Austin, Stanford University, the University of California, Berkeley, and Connecticut College in New London, Connecticut where one patch user experienced a blood clot in her lung last spring.

In addition “Lee Shulman, incoming board chairman of the Association of Reproductive Health Professionals, says he expects that ‘there will be a decrease in use’ of Ortho Evra, at least over the next several months. He adds that he has been inundated with doctor and patient phone calls asking whether the patch is safe to use.”

A number of litigation attorneys we spoke with, who are familiar with pharmaceutical litigation, agreed that it is becoming more difficult for doctors and major healthcare providers like colleges and universities to ignore the mounting evidence and warnings and simply write thousands of prescriptions for the patch. The percentages indicate that when that many prescriptions are written some of the women will suffer serious or fatal adverse reactions.

There are also many well-publicized law suits alleging deaths and catastrophic injuries from the very side-effects contained in the November 2005 warning. Thus, any doctor writing a prescription for the patch from that point on is doing so at his or her peril. Given the potentially fatal side-effects of the drug, writing a prescription now could be considered irresponsible in terms of good and accepted medical practice especially if an otherwise healthy woman is paralyzed or dies from a stroke caused by blood clots after using the patch.

Thus, it is not surprising that so many healthcare providers are rethinking their policies and recommending alternative medications to their patients.

In mid-November another high-profile wrongful death case was commenced against Ortho-McNeil and Johnson & Johnson. It involves Alycia Brown, an eighth-grader in La Crosse, Wisconsin, who died of blood clots in her lower pelvis on May 7, 2004. She had been using the Ortho Evra birth control patch for about eight weeks.

The federal law suit filed in Madison by her parents claims the patch was the cause of their daughter’s tragic death. The La Crosse County medical examiner has found that Ortho Evra was a likely contributing factor in Alycia’s death.

Although many lawsuits have already been commenced against Ortho-McNeil and its parent company, Johnson & Johnson, for injuries and deaths allegedly caused by the patch, the 14-year-old is now the youngest known victim.

As Lorie Brown, Alycia’s grieving mother, told reporters:  "I'm out to let people know: get off (Ortho Evra). That's my biggest goal here. I didn't save her life, but maybe I can save somebody else's." It seems that many responsible doctors and major healthcare providers are trying to do the very thing.

Many experts, consumer watchdog groups, and critics of the FDA drug approval process in general, and Ortho Evra in particular, believe the dangers presented by the patch should have been obvious to the FDA before the drugs approval. They are also concerned by the FDA’s position that it intends to do nothing at present because it considers the information regarding the risks posed by Ortho Evra merely “preliminary.”

(Sources: HoustonChronicle.com, Public Citizen – Worst Pills Best Pills; CBS News; Associated Press; Food and Drug Administration Web Site; Wall Street Journal; Newsinferno.com Archives)

• Oral Controlled-Release
• Coated-Bead
• Diffusion
• Reservoir
• Chewable Tablets
• Rapid Disintegration
• Buccal
• Effervescent
• Polymer-Based

• Infusion devices
• IV Administration Sets
• IV Pumps & Controllers
• IV Catheters
• Premixed IV Solutions
• Hypodermic Products
• Prefilled Syringes
• Hypodermic Syringes
• Hypodermic Needles
• Gene/Protein Delivery Systems
• Hemodialysis 
• Peritoneal Dialysis 
• Enteral Feeding Products

• Dosage Formulations
• Metered Dose Inhalers
• Dry Powder Inhalers
• Nasal Spray Dispensers
• Ventilators
• Nebulizers

• Transdermal Drug Delivery Systems
• Implantable Drug Delivery Systems
• Pulse Generators
• Drug Inserts
• Drug-Eluting Stents

• Respiratory Agents
• Central Nervous System Agents
• Cardiovascular Agents
• Digestive & Genito-Urinary Agents
• Hormones & Related Agents
• Anti-Cancer Agents
• Anti-Infective Agents
• Vitamins & Related Preparations
• Biologicals

• injectable drugs: nanotechnology promises to create new dosage forms that are easier to administer, more pleasant for the patient, and more competitive in the marketplace.
• implantable delivery systems often preferable to the use of injectable drugs since injectables often display initial blood concentration that goes up rapidly (then may fall exponentially) thereby causing potential difficulties with toxicity, and diminished efficacy as the drug concentration falls below the targeted range. 
• oral drug delivery systems remain preferable (to patients) to implantables or injectables. Thus, development continues with respect to traditional oral delivery systems with nanoengineered improvements.
• (rapid) topical delivery of active compounds. Given their very small size, nanoparticles are able to enter human tissues and cells quickly.
• transdermal systems: Since the number of FDA-approved polymers available for use on skin is increasing rapidly, new opportunities are presented to create new designs with improved ‘on-skin’ properties and diffusion of active molecules compared to current transdermal patches.
• toxin removal. Colloidal dispersions have been demonstrated to remove potentially lethal compounds from the bloodstream, including high concentrations of lipophilic therapeutics, illegal drugs, and chemical and biological agents.

• A history of heart attack or stroke
• Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
  A history of blood clots in the deep veins of your legs
• Chest pain (angina pectoris)
• Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina Unexplained vaginal bleeding (until your doctor reaches a diagnosis)
• Hepatitis or yellowing of the whites of your eyes or of the skin (jaundice) during pregnancy or during previous use of hormonal 
• Contraceptives such as ORTHO EVRA, NORPLANT [levonorgestrel], or the birth control pill
• Liver tumor (benign or cancerous)
• Known or suspected pregnancy
• Severe high blood pressure
• Diabetes with complications of the kidneys, eyes, nerves, or blood vessels
• Headaches with neurological symptoms
• Use of oral contraceptives (birth control pills)
• Disease of heart valves with complications
• Need for a prolonged period of bed rest following major surgery
• An allergic reaction to any of the components of Ortho Evra
• Women who may be using Ortho Evra should contact their physician if any of the following warning signals develop:
• Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung)
• Pain in the calf (indicating a possible clot in the leg)
• Crushing chest pain or tightness in the chest (indicating a possible heart attack)
• Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke)
• Sudden partial or complete loss of vision (indicating a possible clot in the eye)
• Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your doctor or health care professional to show you how to examine your breasts)
• Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor) Severe problems with sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression)
• Jaundice or a yellowing of the skin or eyeballs accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems)

• Allergies to drugs, adhesive tape, or bandages
• Chest pain from a heart condition (angina)
• Diabetes requiring insulin injections
• Heart attack or heart disease
• High blood pressure (severe)
• Irregular heartbeat (heart arrhythmia)
• Kidney disease
• Liver disease
• Overactive thyroid
• Skin disease
• Stomach ulcer

• Acetaminophen-containing drugs such as Tylenol
• Caffeine-containing drugs such as No Doz
• Certain airway-opening drugs such as Isuprel, Dristan, and Neo-Synephrine
• Certain blood pressure medicines such as Minipress, Trandate, and Normodyne
• Cimetidine (Tagamet)
• Haloperidol (Haldol)
• Imipramine (Tofranil)
• Insulin
• Lithium (Eskalith, Lithobid)
• Non-nicotine quit-smoking drugs such as Zyban
• Oxazepam
• Pentazocine (Talwin)
• Propranolol (Inderal)
• Theophylline (Theo-Dur)

On November 10, 2005, Ortho McNeil, in conjunction with the FDA, issued a warning about the increased risks of blood clots associated with Ortho Evra. In the new warning, Ortho-McNeil admitted for the first time that women who use the patch will be exposed to up to 60% more estrogen than they would be exposed to if they were taking a birth control pill with 35 micrograms of estrogen. The patch is only intended to deliver 20 micrograms of estrogen. The FDA's announcement on this warning can be found at http://www.fda.gov/bbs/topics/news/2005/NEW01262.html. It is widely understood that increased exposure to estrogen greatly increases the risk of blood clots, which can cause serious injury or death.

Venous thrombosis is a blood clot formation in the veins that most commonly forms in the veins of the legs. The thrombus can interfere with circulation; it may break off and travel through the blood stream, which can cause pulmonary embolism or stroke. Treatment may include long term use of anticoagulant medications and/or surgery. The new warnings from the FDA and Ortho-McNeil indicate that the risk of developing blood clots may be significantly higher with the Ortho Evra patch than with oral contraceptives.

Stroke occurs when the blood supply to a part of the brain is suddenly interrupted. In brain tissue, a reduction of blood flow can damage or kill brain cells. Death of brain tissue can lead to loss of the function controlled by that tissue. Stroke is an extremely serious medical condition that often leads to adult disability and death. It is important to identify a stroke as early as possible because patients who are treated earlier are more likely to survive and have better recoveries. The new warnings from the FDA and Ortho-McNeil indicate that the risk of stroke may be significantly higher with the Ortho Evra patch than with oral contraceptives.

It is alleged that Ortho-McNeil was aware of the increased medical risks associated with Ortho Evra before the drug was approved and that, once approved, the company failed to adequately warn patients about these risks. Evidence shows that the risk of blood clots, heart attack and stroke associated with Ortho Evra is significantly higher than with oral contraceptive pills. The incidence of embolisms and thrombotic injuries in Phase III trials of Ortho Evra was reportedly six times greater than the incidence of such events in oral contraceptives using the hormone levonorgestral. The FDA has logged 9,116 reports of adverse reactions to the patch in a 17 month period, whereas Ortho Tri-Cyclen, a birth control pill, only generated 1,237 adverse reports in a six year period. During a 12 month period, 44 serious injuries or deaths have been associated with Ortho Evra, whereas only 17 such reports were linked to the birth control pill during a similar time period. The pattern is further magnified when usage rates are considered: Ortho Tri-Cyclen has six times the number of users as Ortho Evra.

Ortho Evra is an adhesive, transdermal birth control patch that is worn on the torso. The patch is intended to release 150 mcg of norelgestromin and 20 mcg of ethinyl estradiol into the bloodstream per 24 hours. It is replaced once a week for three weeks, and no patch is worn during the fourth week during menstruation. The regimen is then repeated. Ortho Evra was approved by the FDA in November 2001, and over 4 million women have used Ortho Evra since its approval. Ortho Evra continues to be marketed aggressively to both consumers and physicians.

About Parker & Waichman, LLP
Parker & Waichman, LLP is a leading products liability and personal injury law firm that represents plaintiffs nationwide. The firm has offices in New York and New Jersey. Parker & Waichman, LLP has assisted thousands of clients in receiving fair compensation for injuries resulting from defective medications and medical devices. For more information on Parker & Waichman, LLP please visit: (http://www.yourlawyer.com) or call 1-800-LAW-INFO (1-800-529-4636).

CONTACT: Parker & Waichman, LLP
          Jason Mark, Esq.
          Melanie H. Muhlstock, Esq.
          1-800-LAW-INFO
          1-800-529-4636 -- toll-free
          http://www.yourlawyer.com

But the agency said the results are preliminary and do not require immediate action other than advising women to discuss the risk with their doctor.

The results of the study, and another that found no increased risk, were made public Thursday by the patch's manufacturer.

"The results are preliminary and further evaluation is necessary to understand what these results mean," Dr. Daniel Shames, director of the division of reproductive and urological drug products at FDA, said at a briefing.

The finding comes from one of two studies comparing the patch and pill, said Ortho Women's Health & Urology, maker of the once-a-week patch. The Raritan, N.J.-based company is owned by Johnson & Johnson.

Last year an investigation by The Associated Press, citing federal death and injury reports, found higher rates of blood clots in women using the patch.

The first study found no increased risk of clots but the interim results from the second study suggested a twofold increase in the risk of venous thromboembolic events, or clots in the legs and lungs, in women using the patch, Ortho said.

However, because the confidence intervals of the results for the two forms of contraceptive overlap, there actually may be no increased risk from the patch or it may be more than twice, Shames said at a briefing.

He said the risk of a nonfatal blood clot is about one per year in 10,000 women not using a contraceptive. For those using a hormonal contraceptive such as the patch or pill the risk rises to between three and five, he said.

"These are fairly unusual events," said Shames. He noted that in preapproval testing of the patch on about 3,000 women there were two reports of blood clots, but one involved a woman who had had surgery.

The ongoing studies also are looking at the risk of heart attacks and strokes among users of the two types of contraception. Currently there is no difference but the numbers are small and it will take another 18 months to see if a difference occurs, Shames said.

The company said that the risk of clots remains rare and that they have been reported as a potential risk of all hormonal contraceptives.

Release of the interim results comes four months after the Food and Drug Administration warned women that the increased levels of hormones released by the patch put them at higher risk of blood clots and other serious side effects. Ortho said it shared the results of the latest studies with the FDA.

Additions to the patch label made in November warned women that they would be exposed to about 60 percent more estrogen than those who use birth-control pills.

Since the patch went on sale in 2002, more than 4 million women have used it.

The investigation by The Associated Press found that patch users die and suffer blood clots at a rate three times higher than women taking the pill. About a dozen women died in 2004 from blood clots believed linked to use of the patch, the AP reported. Dozens more suffered strokes and other clot-linked problems.

Health officials warn that women who smoke should not use the patch, since smoking increases the risk of stroke and heart attack.

"We're not sure what this means clinically, but it's information that people need to know about," said Dr. Daniel Shames, who heads the Food and Drug Administration division that evaluates contraceptives.

Blood clots usually form in the legs, and sometimes, the lungs. They can travel to the heart or the brain, causing heart attacks and strokes. But the overall risk of blood clots among women taking birth control pills is low, about three to five cases for every 10,000 women treated for a year.

"At this time, we do not plan on taking any specific regulatory action based on these preliminary results," Shames added.

Manufacturer Ortho-McNeil Pharmaceutical, Inc. said it is cooperating with the FDA in the ongoing scientific investigation. The company, a division of Johnson & Johnson, sponsored the research that is raising concern. Sales of the patch totaled more than $400 million in 2004, according to DrugTopics.com, an industry website.

Marketed as Ortho Evra, the birth control patch has been used by more than 4 million women since the FDA approved it in late 2001. It works by releasing estrogen directly into the bloodstream through vessels near the surface of the skin. While contraceptive pills have to be taken daily, a woman can wear one patch for seven days.

Since estrogen can promote the formation of blood clots, women taking any hormonal contraceptive run the risk of such side effects. But with the patch, the total level of estrogen exposure is 60% higher than with a typical birth control pill, according to the FDA.

"Because it is absorbed directly through the blood as opposed to a pill taken by mouth...the total exposure is more," said Shames.

The FDA issued a warning last November about the higher levels of estrogen with the patch. The latest worries come after two separate safety studies commissioned by the manufacturer produced seemingly contradictory results.

A recently published study by the Boston Collaborative Drug Surveillance Program found no higher risk of blood clots among women using the patch than among those taking the standard dose of birth control pills.

But preliminary findings from a second study, by i3 Drug Safety, found a two-fold increase in the risk of blood clots in the legs and lungs for women using the patch. Complete data from the second study has not been publicly released.

Both studies used insurance claims data to track the experiences of tens of thousands of women using the medications. Researchers also were looking into whether women using the patch face a higher risk of heart attacks and strokes, although preliminary data suggest that they do not, the company said. FDA officials said long-term studies may be needed to pinpoint the risk.

Last year, an Associated Press analysis of FDA reports of serious drug side effects indicated that women using the patch faced a three times higher risk of dying or suffering a blood cut than those taking birth control pills.

Some critics of the agency say the potential for harm should have been clear in clinical trials before the patch was approved.

"It is no more effective than the pill and has a higher risk because it delivers significantly more estrogen," said Dr. Sidney Wolfe of the Public Citizen advocacy group.

The FDA's Shames said the drug was tested on 2000-3,000 women before it was approved, and two suffered serious blood clots. One patient had undergone surgery, he said, so it was unclear if her problems could be blamed on the patch. "Statistically, it had no meaning," said Shames.

But the Associated Press reported that at the time that the cases had alarmed an FDA drug reviewer, who recommended that patients and doctors be clearly advised of the risk, and follow-up safety studies be conducted.

Susan Wood, a former head of the FDA women's health office, said the agency "still doesn't have enough data to make a call" on the safety of the patch.

Wood said women using the patch should weigh the new information on risks against their individual circumstances, including their health and how they use birth control. Wood resigned from the agency last year to protest delays in approving the "morning after" contraceptive for sale without a prescription.

"Women should be aware that (the patch) does have a higher estrogen level and this potentially can lead to greater side effects," she said. "But the increase in risk, even if real, would still be fairly low. This is more information that is helpful, but it is not something that should send women off their birth control method."

Injured by the Ortho Evra Patch?