http://www.latimes.com/news/nation/reports/fda/lat_propulsid001220.htm
PROPULSID: A Heartburn Drug, Now Linked to Children's Deaths
Wednesday, December 20, 2000 | Print this story
PROPULSID:
A Heartburn Drug, Now Linked to Children's Deaths
Once evidence of harm emerged, FDA took years to withdraw approval.
By DAVID WILLMAN, Times Staff Writer
Tina and Jeffrey A. Englebrick of Shawnee, Kan., mourn their
3-month-old son, Scott, who died in 1997 after taking the heartburn
drug Propulsid. The FDA "took my kid as a guinea pig to see if it
would work," Jeffrey Englebrick says.
BRIAN WALSKI / Los Angeles Times
In mid-1993, FDA officials prepared to approve Propulsid, a drug
that eased nighttime heartburn. But a sign of danger loomed.
FDA medical officer Andre Dubois noted that 48 of 1,993, or
2.4%, of the patients who took Propulsid in U.S. studies experienced
"heart rate and rhythm disorders." In addition, eight children age 6
or younger who were given Propulsid had died.
Dubois found that the drug's chemical makeup could disturb
cardiac function. But he agreed with drug maker Janssen
Pharmaceutica, a Johnson & Johnson Co. subsidiary, that the deaths in
the studies were attributable to other causes.
He recommended approval along with disclosure in the label of
potential cardiac effects. "The risk seems very low," he said.
Dubois, however, worked in a division that focuses on drugs for
the gastrointestinal tract.
No one at the FDA consulted with the agency's division of
cardiac specialists before approving Propulsid on July 29, 1993,
according to physicians familiar with the matter. By not tapping
their expertise, FDA officials failed to notice what should have been
another warning flag: Electrocardiograms showed that Propulsid
prolonged patients' "QT interval," the time during which the heart's
main pumping chambers contract and then relax.
If the QT interval--typically about 4/10 of a second--is
extended even slightly, it can trigger a disruption or cessation of
the heartbeat. Called an arrhythmia, it can result in sudden death.
FDA officials outside the gastrointestinal division had already
warned publicly--on June 11, 1990--that two allergy drugs, Seldane
and Hismanal, prolonged the QT interval and therefore posed lethal
risk. Both drugs were later withdrawn.
Indeed, the danger had been stressed for several years by Dr.
Raymond J. Lipicky, director of the agency's cardiology division.
Lipicky, writing in the August 1993 issue of the American Journal of
Cardiology, said if a drug that prolonged the QT interval had a
benefit that was "less than lifesaving . . . any risk of death would
likely be considered unacceptable."
"Those of us here at the FDA who are aware of your loss wish to again
extend our deepest sympathy and sincere condolences to you and your
family."
- FDA Administrator Florence Houn, writing July 27, 2000, to the
mother of 9-month-old Gage E. Stevens, who died on Thanksgiving 1999.
In approving Propulsid, the FDA agreed to labeling that advised
doctors of "rare cases" of increased heartbeats. The labeling said
Propulsid's role in the events "was not clear."
In response to written questions, Dr. Janet Woodcock, director
of the FDA's drug review center, said the danger associated with
non-cardiac drugs that prolonged the QT interval "was not well
appreciated" at the time Propulsid was approved. Consequently, she
said, this "was not identified as a concern" by the gastrointestinal
division.
By early 1995, Propulsid's danger to the heart was certainly
identified as a concern within the gastrointestinal division, agency
records show.
On Jan. 25, 1995, a senior FDA medical officer, Dr. Stephen B.
Fredd, told Janssen executives that recent adverse-reaction reports
showed their drug was prolonging the QT interval, perhaps resulting
in deaths.
According to the meeting summary, "It was the firm's position
that the cases cited by Dr. Fredd were not 'clean' cases, thus making
it difficult to attribute the effect to [Propulsid]." Fredd responded
that "unequivocal evidence" of Propulsid's culpability was unlikely
to be captured outside of a controlled clinical study.
But within a month, the FDA and the company agreed to the first
of five safety-labeling changes that would help keep the drug on the
market over the next five years.
Meanwhile, a significant market for Propulsid emerged in the
treatment of children.
Propulsid was never proved effective or safe for infants, yet it
became the drug of choice for many pediatricians in treating gastric
reflux, a common disorder that is usually outgrown by age 1. Reflux
can impede infants' digestion and, due to their crying, disrupt their
parents' sleep. As with almost all drugs, doctors could lawfully
prescribe Propulsid for any use, or "indication," they chose.
On Aug. 15, 1996, the FDA informed the Johnson & Johnson
subsidiary that Propulsid was "not approvable" for children,
interviews and documents obtained by The Times show. The rejection,
in keeping with FDA practice, was not made public.
Gretchen Stewart holds her son, Gage Stevens, who was 9 months old
when he died after being given Propulsid as part of a pediatric
study. The county coroner concluded that Propulsid was a factor in
his death.
In private correspondence a year later, on Aug. 19, 1997, Dr.
Lilia Talarico, FDA's gastrointestinal drugs division director, cited
"at least" three recently reported deaths among child patients. She
told a company official the agency was considering altering the label
of Propulsid to "contraindicate," or to warn against its use in
infants.
Asked why the FDA did not immediately inform doctors and
patients of the deaths, Woodcock told The Times: "Labeling changes
[advising of infant deaths] were requested by FDA in August of 1997
but were not agreed to by the company until June of 1998."
That revised label did acknowledge "several pediatric deaths"
but left physicians guessing whether Propulsid was the culprit,
saying, "Causality has not been established."
Parents of children who died after taking Propulsid said in
interviews that they had no inkling of danger.
"If I had known that this drug caused cardiac arrhythmias, I
would never have given it to him," said Tina Englebrick, the mother
of 3-month-old Scott, who died in October 1997. The Kansas health
department identified Scott's cause of death as sudden infant death
syndrome.
Had the parents of Gage Stevens, the deceased 9-month-old, "been
informed of a risk of sudden death, they would not have administered
the medication to their son," according to a lawsuit they filed in a
Pennsylvania court on Sept. 10 against the manufacturer and the
doctor and hospital who treated him. Gage, who had reflux, was given
Propulsid within a pediatric study that was approved by the FDA and
performed by researchers at the University of Pittsburgh.
He died at 6:30 a.m. on Thanksgiving 1999. The county coroner
concluded that the death was "directly related" to Propulsid and one
other drug administered to the child. The coroner said Gage "most
probably" had died after suffering a cardiac arrhythmia.
Said Dr. Robert R. Fenichel, who retired this year as deputy
director of the FDA's cardiac drugs division: "It was scandalous that
all of these kids were being treated with [Propulsid]" in the absence
of proven safety and effectiveness.
On March 23, 2000, the FDA announced that Propulsid would be
taken off the market as of July as a normally prescribed drug because
of scores of confirmed heart-rhythm deaths. Overall, Propulsid has
been cited as a suspect in 302 deaths.
FDA administrators now concede that the agency failed to contain
Propulsid's fatal risk.
"We've had a seven-year history with this drug where it's a very
rich opportunity for us to learn," the FDA's Dr. Florence Houn told
drug industry officials in a Webcast on June 22. "One of the things
we have learned is the approved indication for a drug really needs to
[justify] the serious and life-threatening" side effects.
In comments the same month to an FDA advisory committee, Houn
added, "The labeling probably was not effective."
Why did the agency wait so long to seek the withdrawal of this
drug for nighttime heartburn in adults?
"We simply tried a variety of measures," Woodcock said in an
interview. "We have to sort of walk that line: Where do we inform and
where do we intervene by removing a drug from the market? That is a
very draconian step. . . . And so, we do try to avoid that."
Six specialists involved with the FDA's decisions concerning
Propulsid said the volume of prescriptions for reflux in infants
helped keep the drug on the market.
One specialist who sought earlier withdrawal of Propulsid said,
"If it were just the nocturnal heartburn indication we were
considering . . . it's a pretty easy decision" to pull it off the
market. Many alternative therapies existed, including
over-the-counter products like Tums and Maalox and Zantac.
Woodcock, who was appointed to her position 10 months after
Propulsid was approved, said the FDA did not formally weigh the
off-label use while deciding to keep the drug on the market. She
acknowledged that it was prescribed widely for children but said she
relied on pediatricians to make prudent decisions.
"They're aware of the QT-prolongation issue," Woodcock said.
"This isn't as if it's some mystery. . . . They evaluated this and
came to their own conclusions about the risks."
A spokesman for the Johnson & Johnson subsidiary, Greg Panico,
said the company did not promote Propulsid for use by children.
However, he acknowledged that it did make two "educational grants" to
the North American Society for Pediatric Gastroenterology and
Nutrition. The society's literature advised doctors that Propulsid
could be used safely and effectively in children.
Panico declined to say how much money the company provided;
according to the society's Web site, the group has been "generously
supported" by the Johnson & Johnson subsidiary. The society held a
symposium on the use of Propulsid at an October 1998 conference in
Orlando, Fla. A spokeswoman for the pediatric society said the
company's grants came with "no strings attached."
The removal that Woodcock and her aides negotiated this year
allows the continued sale of Propulsid under a "limited access plan."
This authorizes doctors to administer the drug to patients of all
ages who have not benefited from other treatments and who would be
closely monitored.
In September, the British Medicines Control Agency rejected
continued sales of Propulsid there under such conditions, saying,
"Restricted-access schemes . . . are not adequate to protect public
health." The British have warned since 1998 against any use of
Propulsid in infants and cautioned against prescribing it to children
up to age 12.
For her part, Woodcock said she remains "concerned" about the
drug's use among children. A recent agency review found that, while
"no clear evidence" implicated Propulsid as the primary cause of
eight children's deaths before the July 1993 approval, neither was
there enough data to exclude a "role" for the drug in several of
those cases.
As for adult patients who died, Woodcock said, "It's a terrible
thing to happen to somebody who is just taking the drug for
heartburn."
Panico said there remains a place for Propulsid.
"When we made the decision to limit access to the drug, we had
pleas from families of children who are taking this drug to make sure
that these kids can have continued access to it," he said. "So, it's
a balancing act."
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Copyright © 2001 Los Angeles Times
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