The Food and Drug Administration (FDA) is easy to take shots at. They are either too cautious, or not cautious enough. They're either in cahoots with the drug companies or they're stifling the development of important new drugs. Like an umpire, when they do their job correctly, no one notices. A pretty thankless job.

But recently they made a decision that should make us sick to our stomachs--because for many of us, at least at some point in our lives, it will probably do just that.

Zofran, a miracle drug launched by GlaxoSmithKline in 1991 revolutionized the management of chemotherapy-induced nausea and vomiting (CINV). But as of September 15, its label must now include an extra warning: "The use of Zofran (ondansetron) should be avoided by patients with congenital long QT syndrome."

Long QT syndrome is a rare genetic condition (1 in 7,000 people) that can cause an irregular heart rhythm, which in a small number of cases can be fatal. In effect, the warning says that patients who already have a long QT interval shouldn't take this drug. This is like warning people who are allergic to penicillin not to take penicillin. Although this new warning may seem inconsequential, or even trivial, the unintended consequences of this change are anything but.

Until recently, the warning label for Zofran consisted of an ordinary-looking list of potential side effects. One of these was a long QT syndrome. This warning is not unusual--there are well over one hundred medications on the market that also carry warnings for long QT intervals, including common, safe drugs such as Cipro, Adderall, Albuterol, Lexapro, Benadryl and Zithromax.

But the new FDA warning puts doctors and hospitals in a precarious situation--how do they know who not to give the drug to? How can you determine who the 1 patient in 7,000 is? Will an EKG be required before its use? Will doctors write fewer prescriptions? Will hospitals revert to inferior antiemetic drugs? The answer is probably yes to all of these.

Dr. John Dunn, M.D., a consultant in emergency services and Contract Civilian Faculty at the Carl R. Darnall Army Medical Center in Fort Hood, Texas, believes that "physicians working for risk averse medical systems will be pressured to reduce their use of this proven safe drug and increase precautions, including lab test and cardiac monitoring--all because of a few very weak studies."

The FDA cited three clinical studies -- all with deficiencies in methodology--to support their warning. Each study included very small numbers of patients, mostly following general anesthesia (which itself impacts QT intervals). It is impossible to reach valid conclusions from substandard clinical trials; therefore any assessment of real risk cannot me made. Incidentally, no one in any of the trials was harmed by the drug.

Considering that Zofran has been on the market for twenty years, with more than five million patients safely treated, the data from the above studies appear to be pitiful. Yet, this was enough to trigger the FDA's new warning. It would seem that they are redefining the term "overly cautious." But in doing so, they opened up a door that should remain closed.

Now, if any patient taking Zofran has a bad outcome--whether it has anything to do with the drug is irrelevant--it will be an easy target for trolling lawyers. They will claim that the hospital should have known that Patient X was harmed because he was not "properly evaluated" beforehand. And class-action lawsuits will surely follow. A Google search on "Zofran lawyers" and "Zofran lawsuits" already reveals almost two thousand hits.

For many cancer patients, the most feared side effect of chemotherapy is nausea and vomiting. Depending on the regimen, it can be devastating -- so much so that as of twenty years ago, one-fifth of patients discontinued or delayed their treatments, making this a grave problem. And, until 1991, doctors did not have the tools to do much about it. Antiemetic drugs to combat CINV were either not effective, rife with side effects, or both.

Some over-the-counter antihistamines (Benadryl, Dramamine and Bonine) were previously used for controlling CINV, but for even mildly emetogenic (vomit inducing) chemotherapy regimens, they were ineffective and are rarely used today. Prescription antiemetics were more potent, but they had their own limitations. They did not adequately control CINV in patients receiving highly emetogenic chemotherapy. Furthermore, these drugs are powerful neuroleptic agents (capable of affecting the brain). The most common, Compazine, Reglan, and Haldol, can cause neuromuscular disorders that result in involuntary or impaired body movements and involuntary contraction or cramping of muscles.

This is what cancer patients had to look forward to. That is, until 1991, when Zofran hit the market.

Zofran selectively blocks serotonin type 3 (5-HT3) receptors that are found both in the brain and also in the upper gastrointestinal tract. Under certain circumstances serotonin is released and binds to these receptors, triggering a cascade of biochemical events resulting in nausea and vomiting. Blocking this binding short-circuits the process.

As such, it has had a profound impact on managing CINV. According to Michael S Simon, M.D., M.P.H., a professor of oncology at the Karmanos Cancer Institute at Wayne State University. "Antiemetic therapy has come a long way since the introduction of Zofran," he says. "It has improved our ability to give patients a full course of treatment, thus saving countless lives. Patients are much more comfortable without the extreme nausea and vomiting they suffered prior to its availability."

The drug has other indications: it controls post-operative nausea and vomiting and decreases hospital admissions of dehydrated children suffering from prolonged vomiting. Dr. Dunn says, "We see hundreds of kids every month at our emergency department. The nurses have the authority to administer Zofran -- one of the safest drugs we have --for vomiting kids as young as 2 months right at the door." He adds, "By the time I see the kids, they are already feeling fine and sucking on a Popsicle."

John Fisch, M.D., a senior obstetrician at Magee-Women's Hospital at the University of Pittsburgh Medical Center says, "Zofran is our silver bullet. It is highly effective in treating morning sickness in pregnant women -- even the worst form, Hyperemesis Gravidarum, which causes intractable nausea and vomiting. Zofran is literally the difference between night and day." The FDA classifies Zofran as a class B drug, meaning it is considered to be safe for the fetus.

The new warning will create some additional problems that are not so apparent. Even if doctors and hospitals, in spite of the warning, decide to continue to use the drug as before, there may be a much bigger problem--it may no longer be available. Zofran is now generic and is thus, much cheaper. Good news? Maybe not.

There are now about 250 common (and essential) drugs that are no longer available in the US--mostly generics with a low profit margin. These drug shortages, which have been widely publicized this year, have caused many adverse outcomes, including deaths. This could easily be the case here.

Why would a generic company bother to make the investment to start manufacturing generic Zofran at all when it will probably be a low profit item with unknown, but significant liability issues attached to it? Startup costs and time to begin manufacturing a new product can be prohibitive. Add in a long wait for FDA inspection of the facility--sometimes two years-- to the liability issue and it could be a showstopper. It is quite possible that no company will be interested in making it, and Zofran will join the list of missing drugs.

That would mean returning to a time when chemotherapy patients would again endure uncontrolled CINV, possibly stopping their treatment; women would suffer needlessly through difficult pregnancies; patients might wake from surgery and vomit for a day; and sick toddlers would have to be admitted to a hospital for painful IV rehydration, rather than going home--mostly due to the fear of lawsuits brought upon by a needless FDA warning.

This is enough to make me sick. Luckily, I have a bottle of some great little pills at home. Maybe you ought to stock up too, just in case.