Major litigation takes aim at Propulsid.

A 61-year-old woman goes to the emergency room with symptoms of severe gastroesophageal reflux disease (GERD), a backflow of stomach acid into the esophagus. The emergency room physician decides to prescribe cisapride--a drug manufactured to treat adults with heart-burn due to GERD--but checks first with the woman's primary care physician, who agrees with the treatment only if an electro-cardiogram (EKG) shows that the woman's heart is functioning normally.

The EKG shows no irregularities, and the patient has no history of heart problems, so she is given the drug. She returns to the emergency room six hours later and dies of cardiac arrhythmia.

An estimated 30 million prescriptions have been written for cisapride since Janssen Pharmaceutica, Inc., a subsidiary of Johnson & Johnson Co., began marketing the drug in the United States under the name Propulsid in the early 1990s. Since 1999, scores of products liability lawsuits have been filed against the drug manufacturer in state and federal courts.

The cases claim that Propulsid is an unreasonably dangerous product and that Janssen purposefully understated the hazards associated with it. They also allege that the manufacturer fraudulently misrepresented a number of facts regarding the drug, including details about testing and the severity and frequency of adverse side effects.

Federal multidistrict litigation (MDL) is underway in the U.S. District Court for the Eastern District of Louisiana in New Orleans, where cases filed in most state and federal courts have been transferred. The MDL was created last August to consolidate the large number of cases filed nationwide. Most pending and future Proplusid cases will become part of it.

Attorney Daniel Becnel Jr. of Reserve, Louisiana, filed one of the first Propulsid cases in the United States and the petition to establish the MDL. At press time, he said that the MDL involves over 500 cases and that most attorneys have not yet filed all their claims. According to Russ Herman of New Orleans, liaison counsel for the plaintiffs and a former ATLA president, as many as 80 lawyers from 40 law firms are part of the litigation.

In addition to the multidistrict litigation, class action lawsuits are pending in several states, including New Jersey, where Janssen is headquartered. The New Jersey Supreme Court designated all pending and future Propulsid litigation statewide as a mass tort last September. (In re Propulsid Litigation, No. Case Code 247 (N.J. Sept. 11, 2000).)

All the lawsuits are products liability cases against Janssen and Johnson & Johnson. About 30 percent also involve medical malpractice claims that allege that a physician should not have prescribed Propulsid because it was contraindicated, that a physician failed to recognize cardiac arrhythmia and continued to prescribe the drug, or that a physician continued to prescribe the drug in combination with other drugs despite warnings of adverse interactions.

Where can plaintiffs file suit? "There are options," said attorney Barry Hill of Wheeling, West Virginia, who filed the claim involving the 61-year-old woman who died shortly after taking Propulsid. If the suit names Janssen and a physician, a pharmacist, or a Janssen employee--such as a drug sales representative--who are citizens of the same state as the plaintiff, the case can be filed in state court and probably stay in state court. If only Janssen is sued, the lawsuit will be removed to federal court and transferred to the MDL in New Orleans. "That's an absolute," said Hill, who chairs ATLA's Propulsid Litigation Group, is lead counsel in class action litigation in West Virginia, and is involved in the federal multidistrict litigation.

Cases filed in New Jersey against just the manufacturer can be filed in state court and stay there because Janssen's headquarters are located in New Jersey.

The FDA approved Propulsid for marketing in the United States in 1993. Beginning in 1995, Janssen worked with the agency to issue labeling changes to clarify warnings on package inserts. The FDA also ordered the manufacturer to issue the first of four "Dear Doctor" letters, alerting physicians of the labeling changes.

In June 1998, after the agency received reports of cardiac arrhythmia and other serious cardiac problems associated with Propulsid, it ordered Janssen to revise the label to include instructions that doctors consider EKGs for patients to whom they prescribe the drug.

In January 2000, in response to reports of 270 incidents of serious heart rhythm abnormalities, including 70 deaths, the FDA ordered Janssen to change the warning label to require doctors to perform EKGs and certain blood tests before prescribing Propulsid.

By last March, Propulsid-related deaths had risen to more than 100, and Janssen announced that the drug would be taken off the market, except in special circumstances, in July 2000.

What went wrong?

Studies have shown that Propulsid users are at risk of developing cardiac arrhythmia, which can lead to fibrillation and perhaps severe brain damage or sudden death. Symptoms may surface mere hours or several years after a patient begins taking the drug.

"It's not a matter of how long a person took Propulsid. It's how much Propulsid was in the blood at any one given time," said Hill. "The more Propulsid you have in your system, the greater the likelihood that it is going to prolong the amount of time it takes the heart to recover after each beat." Hill said the manufacturer has yet to admit this problem.

Like many other drugs, including certain antibiotics, antifungals, and antidepressants, Propulsid is metabolized by a liver enzyme. If a person takes more than one of these drugs, they compete for the enzyme, and only some of each drug will be metabolized, leaving the remainder to linger in the bloodstream.

"This can go on to where you have an overload of the drug in your blood without ever having taken an overdose. The higher the cisapride level in the blood, the more likely it will lead to arrhythmia," Hill said.

Court documents Janssen filed state otherwise. "Propulsid is quickly metabolized and eliminated from the body," the drug maker said.

The history of Propulsid is steeped in disagreement. According to Hill, transcripts of FDA hearings document arguments between agency scientists and Janssen over the labeling changes. Some disagreements involved changes the FDA thought were needed. Others were about changes that Janssen wanted to make that regulators thought were potentially misleading.

The company's "Dear Doctor" letters "didn't give a full explanation [of the side effects] in the beginning, and the question `When did Janssen know what it was ultimately to report in these letters?' is something we can only speculate on now but will find out during discovery," Hill said.

He added that determining "who knew what and when" is at the heart of the litigation. "What you can say with certainty is that the FDA knew less than Janssen," he said. "Janssen should have known--and almost had to have known--when it first marketed cisapride that it would compete with other drugs on the market for the liver enzyme. That fact was well known in the scientific community."

The first signs of cardiac problems associated with cisapride were reported in the British Medical Journal in 1992, before the drug was put on the U.S. market. (S. Olsson et al., Tachycardia During Cisapride Treatment, 305 Brit. Med. J. 748 (1992).) Hill said, "One would think that knowledge that is available in the scientific community is available to a major drug manufacturer. And if the manufacturer didn't have that knowledge, that is because it chose not to have it."

John Restaino, an attorney in Newport Beach, New Jersey, agreed. "The manufacturer made no effort whatsoever in the initial distribution of the drug to warn of problems. It disclosed none of the problems to the FDA, it did not share with doctors information that it had, it did not share the concern the FDA had." Restaino is handling Propulsid cases involving infant deaths.

Injuries in newborns

Infants were given the drug as treatment either for GERD or for regurgitation. Most were premature newborns whose enzyme systems were not mature enough to metabolize the drug quickly. They suffered the same health problems adult users did, only more severely.

According to Restaino, the FDA and Janssen exchanged letters regarding the use of the drug in infants since at least 1996, when the agency told Janssen that Propulsid was not indicated for treatment of any condition in infants and that the data it submitted on testing the drug in infants were inadequate. In 1997, the FDA told Janssen that the use of cisapride in children was off-label.

Problems associated with the use of Propulsid in infants were known well before then, Restaino said. A study published in the British Medical Journal in 1992 linked the drug with rapid infant heart rates. Similar articles in other journals followed.

The results of an 18-year Italian study published in 1998 in The New England Journal of Medicine showed that infants who took cisapride and developed cardiac arrhythmia had a slightly more than 41 percent risk of developing Sudden Infant Death Syndrome (SIDS). (Peter John Schwartz et al., Prolongation of the QT Interval and the Sudden Infant Death Syndrome, 338 New Eng. J. Med. 1709 (1998).)

Challenges

According to Hill, Janssen's primary defense focuses on causation. The company claims that once Propulsid is fully metabolized, it cannot cause problems.

"Now is that true? The company has no studies to back that up," said Hill. "Our information is that Janssen is doing those studies now, after the drug is off the market, but it certainly didn't have studies like that at the time the drug was being sold."

Plaintiffs will also encounter the learned-intermediary doctrine for injuries and deaths that occurred after Janssen sent the "Dear Doctor" letters. Hill said, "The company's position will be, `We didn't know about any problems until we sent out the first letter. We are absolved of responsibility for everything we warned about in that letter. We didn't know anything more until we sent out the second letter. The learned-intermediary doctrine should protect us from what we warned about in that letter,' and so on for all four letters."

Plaintiffs may attack the defense by pointing out that Janssen's widespread direct-to-consumer marketing campaign claimed that Propulsid was safe while the FDA claimed that the campaign was misleading and that it downplayed the dangers of the drug.

Problematic cases involve people who had significant coronary artery disease before they began taking Propulsid and whose problems worsened after taking the drug. Hill said, "Sorting out what might be related to Propulsid from what is simply a continuation of a preexisting coronary artery disease is difficult."

Another challenge is proving that plaintiffs who suffered sudden cardiac death did so because Propulsid caused arrhythmia, not because they suffered heart attacks. "This is where autopsies can be important," Hill said. A heart that stopped because of arrhythmia has no telltale damage. A heart that stopped because of a heart attack has recent tissue damage.

Challenging infant cases involve children with multiple illnesses. Restaino said, "It's a matter of proving what caused the death--the cisapride and arryhthmia or the child's severe medical disorders."

He also said that although the liability picture in cases involving SIDS deaths is strong, the challenge is that there is no known cause of SIDS, so plaintiff attorneys will have to refute the defense argument that the child died from other causes, such as abuse or accidental smothering.

The makings of a provable case are facts like those in the example of the 61-year-old woman--a person had a normal EKG before Propulsid was prescribed and died of cardiac arrhythmia after taking the drug, said Hill.

As for claims involving infants, Restaino said that a strong case is one where a healthy child was given Propulsid because he or she did not outgrow the tendency to spit up after being fed, the drug did not help, and the infant died. "When the physician prescribed Propulsid, in essence, he signed the child's death warrant," Restaino said.