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Philadelphia Inquirer, 3/5/06
DRUG-PATCH SAFETY TRIGGERS AN FDA PROBE
by Dawn Fallik
In July, the Food and Drug Administration announced an investigation
into 120 deaths caused by fentanyl patches, used for chronic pain.
In November, the agency issued a warning about birth-control patches
after studies showed that women using them had 60 percent more
estrogen in their blood than those on the pill, giving them a higher
risk of potentially fatal side effects.
As a result, the FDA said on Thursday that it was launching "an
exhaustive review" into the safety of patches themselves.
In the last 25 years, patch medications have morphed from a simple
motion-sickness drug to more than 30 different prescriptions used by
12 million people worldwide for ailments ranging from bladder
control to heart disease.
Yet even as companies market more and more versions -- the first
antidepressant patch was approved Monday -- medical experts worry
that patches are unsafe when heated, whether from a high fever or
from soaking in a hot tub.
"Most people don't realize that heat is going to increase absorption
rates, even to toxic levels," said Michael Cohen, director of the
Institute for Safe Medication Practices, an industry watchdog in
Huntingdon Valley. "It's something patients should be warned about."
The experts say that heat increases the absorption rate on patches,
sometimes with fatal consequences.
All patches work the same way: The drug seeps through the skin into
the bloodstream, and increased blood flow causes the body to absorb
the drug faster, said Bozena B. Michniak, who studies transdermal
patch delivery at the Center for Biomaterials at Rutgers
University's Piscataway campus.
But not all hot patches will necessarily cause harm.
"It depends on the drug and the patch," Michniak said. "We could all
say there will be an effect and absorption rate will increase, but
how much? Many factors play a role."
The problem is most evident with the fentanyl patch, which is 100
times more potent than morphine. Since it was introduced in 1990,
the drug has been linked to 120 deaths, the FDA reported.
FDA officials say that as few as 1 percent of all serious side
effects are reported to the agency. Its database does not give
details about the cause of death. The agency has been criticized,
most recently in the recall on the arthritis pill Vioxx, for not
paying attention to problems early on.
Whether a drug comes in a patch or not, the FDA does not say how
many deaths should trigger an investigation or a recall. In 2000,
the agency pulled the diabetes drug Rezulin after it was tied to 63
liver-failure deaths. Lotronex, a drug for irritable bowel syndrome,
was recalled after it was linked to five deaths.
In 2004, patches overall were cited as the primary cause of death in
eight cases, including two teens on birth-control patches, according
to an Inquirer analysis of an FDA database.
In 2003, three people died, including a 45-year-old man and a
58-year-old woman on fentanyl pain patches.
Both years, the patch was a primary suspect in at least 30 cases in
which patients were hospitalized, disabled or left with a
life-threatening complication.
"The problems are real, they're happening and they're
underreported," said Cohen, who sits on the FDA's Drug Safety and
Risk Management Advisory Committee. "It's possible for people to get
hurt."
The FDA database, the Adverse Event Reporting System, is based on
mandatory reports of all kinds of drug reactions from pharmaceutical
companies and voluntary data from doctors and hospitals. The data do
not include whether heat was a factor in the problem, but mention
the name of the drug, and whether it was a primary, secondary or
concomitant factor in the incident.
The FDA database does not indicate with certainty that the suspected
drug caused a reaction. and does not include final investigation
results.
Studies as early as 1986 showed that heat can double the rate at
which the body absorbs medication, but there were no public warnings
until 1994.
That came after the death of a 36-year-old Montgomery County man.
Kurt Hophan was given a fentanyl pain patch after a back injury. He
went to his bedroom at his mother's house in Glenside and fell
asleep with a heating pad and an electric blanket.
"When the heat from the pad and the electric blanket came into
contact with the patch, the amount of fentanyl released into Mr.
Hophan's bloodstream was approximately one hundred (100) times
greater than the amount prescribed," according to the judge's ruling
in a lawsuit filed against the drug's manufacturer by his mother,
Elaine Hophan.
He never woke up. He died on March 4, 1994.
In 2001, a jury awarded his mother $5 million in compensatory
damages. After an appeal, the case was settled under a confidential
agreement, said Stephen Raynes, who represented Elaine Hophan.
The warning appeared three months after Hophan's death. Johnson &
Johnson declined further comment.
* * *
There's no question that there are benefits to patch medication, and
that millions of consumers use patches safely.
They are easier on the body because medicine is absorbed through the
skin into the bloodstream, without a "first pass" through the liver
and the stomach. That often means a smaller dose is required.
Plus, it's convenient.
"Patches improve compliance, particularly for people who have to
take medication several times a day or for people who forget," said
Sean Hennessy, pharmacology professor at the University of
Pennsylvania and another member of the FDA's drug safety committee.
And they are popular. In 2004, patch sales totaled about $3.4
billion, according to Greystone Associates, a medical
market-research firm in New Hampshire.
The patch comes in two main forms: the liquid reservoir and the
matrix.
In the liquid-reservoir version, such as the fentanyl patch, the
medicine is embedded into a gel-like substance in the center, and
released through a membrane into the skin.
The matrix patches contain the medication within the adhesive that
adheres to the skin, often using the flesh as the rate control --
because the skin can absorb only so much, so fast.
The patch is not for every drug, said John Urquhart, professor of
biopharmaceutical sciences at the University of California at San
Francisco and one of the creators of the original motion-sickness
patch.
"A lot of morons out there think you can put a drug in a patch and
it will sell like hotcakes," Urquhart said.
To work well in a patch-delivery system, he said, the drug has to be
effective in small doses. The medicine should not cause irritation
(which increases absorption), and should have a wide safety margin
to prevent accidental overdose that can occur when it is heated.
Multiple studies have shown that heat has a sharp effect. A 1986
study found that just 20 minutes of bicycling with a nitroglycerin
heart medication patch increased concentration of the drug twofold
to threefold. Similar results were found after 30 minutes in a
sauna.
"In chemistry, if we want to speed up a reaction, you apply heat,"
said Robert Middleberg, laboratory director of National Medical
Services in Willow Grove. "It's silly for us to believe that heat
wouldn't play a factor in a drug-delivery device that works with the
skin."
The independent lab receives thousands of unexplained-death cases
from medical examiner's offices nationwide. Of the 100 or so
patch-related deaths he gets each year, about 70 percent are caused
by patient misuse and 15 percent more are due to drug abuse. The
rest, Middleberg said, cannot be explained, and he thinks they are
likely due to a problem with the patch.
"The dynamics of the patches are not really completely understood,"
he said.
Most of the patch-related deaths that Middleberg sees involve
fentanyl.
"You find reports of death with other patches, most notably
nitroglycerin patches," he said. "But they are really hard to prove
because nitro just falls apart in the body and you're left wondering
what really happened."
One company, ZARS Pharma based in Salt Lake City, specifically uses
heat with its patch products, including an anesthetic one approved
by the FDA in June and marketed by a Chadds Ford company, Endo
Pharmaceuticals Holdings Inc.
Their two patch products work differently. The pain patch, under
development, comes with a separate device, similar to a heating pad,
that is placed over it. The anesthetic patch heats up when exposed
to air, much like over-the-counter hand warmers.
Skin temperature is usually about 89.6 degrees Fahrenheit, but
increasing that temperature up to about 102 degrees can quadruple
the absorption rate, said Michael Ashburn, ZARS vice president for
clinical and regulatory affairs. That can happen in as little as 20
minutes, he said.
"You have to be able to control the temperature so we know what's
getting through," Ashburn said.
Although uncontrolled amounts of narcotics, such as fentanyl, could
have fatal results, it's unclear what higher doses of other drugs
could do.
"I don't think you can kill yourself with a nitro patch; you'll just
make yourself feel dizzy," said Gordon Flynn, professor of
pharmaceutics at the University of Michigan and a consultant for
Mylan Pharmaceuticals Inc. "You're not supposed to be on it
continuously."
In December, the FDA began to study how heat affects the absorption
rates of all patches under various circumstances, said Lucinda Buhse,
director of the FDA's Division of Pharmaceutical Analysis.
"We would like to develop a method that's applicable across the
board with different drugs and different patches," she said.
The investigation will focus on fentanyl and birth-control patches
first, to see how they react to hot tub and sauna heat, among other
scenarios.
Douglas Stokke, a spokesman for Johnson & Johnson, which makes the
fentanyl patch and Ortho Evra birth-control patch, said the company
did not have clear information about the FDA study. When asked
whether doctors should warn patients about exposure to heat while
wearing a patch, he said: "Physicians should be knowledgable about
the prescribing information for these products and should be
prescribing them according to labeling."
But, says Michniak, of Rutgers, those who use patches should be
careful about sitting in the sun, using heating pads, or doing
anything else that might increase the skin temperature for a long
time.
"If it's not in the patient insert, they may not be as aware as they
should be," she said.
* * *
One patch whose safety is being questioned is the Ortho Evra
birth-control patch. Last year, doctors wrote more than 9.4 million
prescriptions for it, according to IMS Health, an industry
monitoring firm based in Plymouth Meeting.
In November, the FDA released a study saying that women who wore the
patch had far more estrogen in their bloodstream than those who took
the pill. Researchers aren't sure why. Four months later, Johnson &
Johnson released a study stating that women who wore the patch had
twice the number of blood clots, which can cause strokes and heart
attacks.
On the same day, another study, published in the journal
Contraception, said there was no additional risk compared with the
pill's risks.
Vanessa Cullins, an ob/gyn and vice president for medical affairs
for Planned Parenthood, said the patch came under fire unfairly.
In the J&J study, Cullins noted that rates for blood clots were as
high as four per 10,000 on the pill and eight per 10,000 on the
patch.
Cullins said that, even if the increase were real, "it's still a
very rare event."
Women should weigh the risks and benefits of the patch, she said,
noting that it may not be appropriate for those with a family
history of blood clots or strokes.
Since July, more than 40 lawsuits have been filed nationwide,
claiming that blood clots caused by the patch killed or injured
women.
* * *
While studies into patch safety continue, more proposals for new
transdermal medications are appearing before the FDA.
Next up is Daytrana, a controversial methylphenidate patch
specifically for children with attention deficit hyperactivity
disorder. In June, FDA medical officer Robert Levin said the patch
resulted in "excessive drug exposure at inappropriate times,"
vomiting, and a high risk of causing a tic. He suggested that it not
be approved.
Seven months later, Levin changed his mind. In December, he told an
FDA advisory committee that the patch, aimed at 6- to 12-year-old
children, did not cause significantly different problems than
Concerta, an ADHD pill. With one exception: Up to 22 percent of
those who used the patch became so sensitive to it that they could
never take the drug methylphenidate again, in any form.
The ADHD patch lasts nine hours, and members worried that children
would be responsible for their removal and not take it off in time.
"Theoretically, it is possible that continued exposure could
increase the risk of insomnia and other adverse events," Levin said.
The FDA did not respond to multiple requests to interview Levin and
to questions about the database.
The committee unanimously recommended the patch, but only for
children who cannot swallow pills. It is now under FDA review. |
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