Fw: NYTimes.com Article: Many Drugs Harm the Liver, but Most Remain on the Market

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Many Drugs Harm the Liver, but Most Remain on the Market

>

> By LAURIE TARKAN

>

> It is an unsettling truth, one that people who have to take

> medicine would probably rather not think about: occasionally, with

> little or no warning, prescription and even over-the-counter drugs

> can cause liver damage. Cases are not common, but they can be

> devastating, leading to death or requiring a transplant.

>

> " Drug-induced liver disease is probably the single leading cause

> of drugs' running afoul once they hit the market, " said Dr.

> K. Honig, director of the Office of Postmarketing Drug Risk

> Assessment at the Food and Drug Administration.

>

> Liver failure, also called hepatotoxicity, is rare, affecting

> about 2,000 adults and 90 children a year in the United States. But

> drugs cause about 55 percent of the liver failure cases evaluated

> at liver transplant centers, said Dr. M. Lee of the

> University of Texas Southwestern Medical Center in Dallas, who runs

> a group that surveys about 40 of the centers. But in addition to

> cases of irreversible liver failure are many more instances of less

> serious liver damage that are not recorded, experts say.

>

> Liver problems and deaths have led to several drugs' being taken

> off the market in the last few years, and to others' having

> warnings added to their labels. The problems can be a tremendous

> drain on drug companies, which may be hit with lawsuits and forced

> to withdraw drugs they spent hundreds of millions of dollars to

> develop.

>

> In the last year, the F.D.A. has increased its efforts to prevent

> the problems. It has held drug toxicity workshops for staff members

> who review new drug applications. It is also working with liver

> experts, and it held a conference in February with them and the

> drug industry to develop better ways to identify potentially toxic

> drugs and spot problems once a drug is approved. The proceedings of

> that conference were posted on the F.D.A.'s Web site, www.fda.gov.

>

> The agency's actions were prompted in part by an unusually high

> number of drugs that were found to cause liver failure in the past

> few years.

>

> Most notably, the popular diabetes drug Rezulin, approved in 1997,

> caused about 90 cases of liver failure, including 63 deaths, before

> it was withdrawn in March 2000.

>

> A year earlier, the antibiotic Trovan was severely restricted

> after 14 cases of acute liver failure were reported, and the year

> before that, a painkiller called Duract was withdrawn after causing

> four deaths and necessitating eight liver transplants.

>

> Dr. Neil Kaplowitz, director of the University of Southern

> California Center for Liver Diseases, said: " The problem of drugs

> causing injury to the liver has been recognized probably for 50

> years. But the attention that has been focused on Rezulin has put

> the spotlight on it. "

>

> More cases are brought on by acetaminophen, the ingredient in

> Tylenol and many other products used for pain and fever. Each year

> it causes acute liver failure in nearly 800 people who take more

> than the recommended dose (including those who intentionally take

> an overdose). Most recover; in 1999, 85 died.

>

> The F.D.A. is also looking into how to reduce the risk of liver

> toxicity from acetaminophen, said Dr. Temple, the associate

> director for medical policy for the drug evaluation and research

> center of the F.D.A.

>

> Children are as susceptible to liver injury as adults, although

> the incidence is lower in children because they take fewer

> medications.

>

> The liver is particularly vulnerable to drugs because one of its

> functions is to break down or metabolize chemicals that are not

> water soluble. Most drugs fit that description.

>

> " The liver has a machinery of enzymes that converts drugs into

> more water-soluble forms that can then be excreted, " Dr. Kaplowitz

> said. But, he added, sometimes the breakdown products are toxic to

> liver cells.

>

> Normally, the liver detoxifies these poisons before they can harm

> it. Indeed it is surprising, given the noxious chemicals that the

> liver is exposed to, that more drugs do not damage it.

>

> " It's a tribute to the fact that the liver has an incredible

> capacity to defend itself, " Dr. Kaplowitz said.

>

> But in a few people, something goes awry. Either the liver churns

> out excessive toxins, or its ability to get rid of them is

> impaired. The toxins in turn destroy liver cells. While a majority

> of cases are mild to moderate, in about 10 percent of people the

> reaction is severe, resulting in coma, multiple organ failure and

> death, Dr. Kaplowitz said.

>

> The fact that liver damage from drugs is rare and random is what

> makes it difficult to prevent. Acetaminophen, in fact, is the only

> common drug for which toxicity is predictable and therefore

> preventable. When taken at a high enough dose, it will cause liver

> toxicity in everybody. Taking more than the recommended daily dose

> overloads the liver and causes it to begin using an enzyme,

> cytochrome p450, that breaks down acetaminophen into toxins.

>

> The maximum dose of acetaminophen for adults is 4,000 milligrams a

> day, or eight extra-strength tablets. Children's doses are much

> smaller, and vary by weight and age; a 4-year-old, for instance,

> should never be given more than 1,200 milligrams a day.

>

> Adults who are chronic drinkers (having three or more drinks a

> day) risk liver injury if they take more than 2,000 milligrams a

> day. Chronic drinking raises background levels of cytochrome p450

> in the liver, so that when a drinker also takes acetaminophen, more

> of the drug is metabolized into toxins than in nondrinkers.

>

> The reason adults die from acetaminophen poisoning is that many

> perceive the drug as safe and take too much, or do not consider

> themselves chronic drinkers.

>

> In children, problems occur when they are given the drug too

> often, or in adult doses, or for too many days, which may cause the

> drug to build up.

>

> " If a child has a fever longer than 24 to 36 hours requiring

> 4-hour to 6-hour dosing of Tylenol, talk to your doctor to make

> sure the child doesn't have a more serious illness, and for help

> with dosing properly, " said Dr. Rob Squires, an expert in pediatric

> hepatotoxicity at the University of Texas Southwestern Medical

> Center.

>

> The American Liver Foundation believes the current warnings on

> acetaminophen labels do not adequately convey the risk to the

> liver.

>

> With most other drugs, however, liver injury is unpredictable and

> therefore more difficult to prevent. A vast majority of people can

> take potentially harmful drugs without any problem, as was the case

> with the 1.5 million who took Rezulin. But a very small percentage

> - 1 in 10,000, or even fewer - will have a serious liver injury.

> Experts theorize that these people may be genetically predisposed

> to liver toxicity.

>

> The liver can also be injured by taking two or more drugs that

> interact poorly. The drugs may compete for the same enzyme.

>

> " If the enzyme isn't around for the second drug, it can rise to

> dangerously high levels, or it can be metabolized by enzymes not

> normally used, and that can lead to a toxic metabolite, " Dr. Lee

> said.

>

> Researchers are frustrated that they cannot accurately predict

> which drugs will harm the liver. Clinical trials are not large

> enough to find such a rare reaction.

>

> " You can't do a trial that's going to pick up a 1 in 50,000

> reaction, " Dr. Lee said.

>

> So researchers look for milder reactions in the trials, like

> elevated liver enzymes, but experts disagree about how accurate

> this marker is, and sometimes drugs that raise liver enzymes get

> approved anyway.

>

> " We're wrestling with the fact that liver enzyme elevations may

> not be completely predictive of more severe events, " Dr. Honig

> said. " If you look at other drugs that have the ability to raise

> liver enzymes, some of them don't ever cause liver disease. "

> Examples include an Alzheimer's drug, Tacrine, and even chronic use

> of aspirin.

>

> The critics contend, however, that reviewers should heed these

> markers, however flawed. " With Rezulin, we happen to think that the

> signals were there, but they were ignored, " said Larry D. Sasich of

> the Public Citizen Health Research Group in Washington.

>

> A clearer signal of potential toxicity is elevation of enzymes

> along with high levels of a substance called bilirubin, a sign of

> liver dysfunction. The combination is thought to carry a 10 percent

> risk of progressing to acute liver failure. Usually drugs that

> cause both elevations are not approved unless the benefits far

> outweigh the risks.

>

> That was the case with isoniazid, a drug that treats tuberculosis,

> and causes liver failure at a far greater rate than Rezulin did.

> " Isoniazid is such a superior drug to anything else we have,

> there's no rationale or compelling argument for withdrawing it, "

> Dr. Kaplowitz said. Likewise, the F.D.A. was reluctant to remove

> Rezulin from the market because it helped over 1.5 million

> diabetics, and it was not withdrawn until two similar drugs, which

> did not cause liver problems, came onto the market.

>

> " You're willing to accept a certain risk if you're weighing it

> against something that's fatal, " said Dr. Eugene Schiff, the

> director of the Center for Liver Diseases at the University of

> Miami School of Medicine. For this reason, many drugs with the

> potential to cause liver trouble remain on the market with warnings

> and recommendations that patients be monitored with periodic liver

> function tests.

>

> But even monitoring is controversial.

>

> " There's a great debate whether monitoring of certain drugs saves

> lives, " said Dr. Temple of the F.D.A. " We know it's burdensome,

> people don't like to do it, and you can go from normal to horribly

> abnormal in between tests. "

>

> The F.D.A., for instance, has recommended that people taking

> statin drugs to lower cholesterol get periodic liver function

> tests. The advice is based on a clinical trial that found

> significant enzyme elevations in about 3 percent of patients. But

> in daily use, these drugs have rarely been associated with liver

> problems.

>

> " People have suggested that the warning is overdone in these

> drugs, " Dr. Temple said.

>

> Until researchers uncover better markers for drugs that can damage

> the liver or pinpoint who is vulnerable, many potentially useful

> drugs will not be approved, and a handful of others will be

> withdrawn.

>

> In the meantime, some experts recommend that patients wait a year

> or two before taking a newly approved drug unless it has important

> advantages over older ones. This is enough time for cases of liver

> failure to emerge. The elderly and people with hepatitis or H.I.V.

> should be especially vigilant because they may be at greater risk.

>

> Certain vitamins and herbs are known to cause liver injury in high

> doses, like vitamin A, germander, chaparral leaf, comfrey, jin bu

> huan, ma huang, valerian, mistletoe and pennyroyal. Cocaine and

> Ecstasy are also known to cause problems.

>

> The symptoms include fatigue; fever; pain below the right rib

> cage; yellowing of the whites of the eyes, nail beds or skin;

> lethargy; and slurring of words.

>

> " The people who really die from these drugs, " Dr. Lee said, " are

> the faithful compliant patients who continue to take a drug even

> after symptoms arise. "

>

>

http://www.nytimes.com/2001/08/14/health/anatomy/14LIVE.html?ex=998903048 & ei

=1 & en=c127321f3b89f23d

>

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