Companies that produce a group of powerful antibiotics are being encouraged by the federal government to move into the pediatrics market, even though the drugs’ use for children has been discouraged for a decade because of severe side effects.
The Food and Drug Administration in March approved the use of ciprofloxacin, or Cipro, for some kidney and urinary tract infections in children under 18, in the event other antibiotics failed to work.
And two clinical trials are under way to demonstrate that another drug, Levaquin, is a safe and effective treatment for pneumonia and middle ear infections in children.
Both Cipro and Levaquin belong to a class of pharmaceuticals called quinolones. The drugs, which include Avelox, Tequin, Floxin and others, have been hailed as life-saving medications that often work when other antibiotics have failed. Hundreds of millions of doses are prescribed every year.
After anthrax spores were released in Florida, New York, Washington, D.C., New Jersey and Connecticut in the fall of 2001, the Centers for Disease Control and Prevention recommended that more than 10,000 people take Cipro as a safeguard.
Johnson & Johnson Corp., which markets Levaquin through its subsidiary, Ortho-McNeil Pharmaceuticals Corp., reported to the Securities and Exchange Commission that Levaquin sales last year were over $1 billion.
But those positive figures, and the risk-benefit calculations that led the FDA to move to open pediatrics markets to quinolones, do not impress thousands of people who say they have suffered adverse reactions from the drugs.
“There are people who are sitting ducks, waiting to have the side effects of these drugs, which are very effective antibiotics that work often for millions of other people,” said Dr. David Flockhart, chief of the Division of Clinical Pharmacology at Indiana University School of Medicine.
Adverse side effects either listed by quinolone manufacturers on drug labels or reported to the FDA’s Adverse Events Reporting System include moderate to abnormal sensitivity to light, grand mal seizures, heart arrhythmia, toxic psychosis and ruptured tendons.
“It’s pure evil,” said John Angell, a Senate staffer who had Achilles tendon injury after taking Cipro in the aftermath of the 2001 anthrax attack.
The fact that quinolones can damage tendons in adults has led some experts to worry about the impact they may have on growing cartilage in children.
Flockhart recalls examining a teen-age girl from the Chicago suburbs after she had been given Levaquin four years ago for a condition that was diagnosed as a sinus infection.
The 35-page FDA-approved label for Levaquin, also known by the generic term levofloxacin, contains the following warning:
“The safety and efficacy of levofloxacin in pediatric patients, adolescents under the age of 18 years, pregnant women and nursing women have not been established.”
The Chicago teen-ager is one of 81 persons from 1 to 17 years old whose adverse reactions to Levaquin, Cipro or Floxin appear in the FDA’s adverse events data base.
These reactions ranged from nausea to coma and cardiac failure, according to the data base. The side effect listed, without explanation, for one 16-year-old girl was “murder.”
The Chicago teen-ager was also 16 when a physician told her mother to give her Levaquin, according to the girl’s sister.
The sister, Mrs. Teri Noto of Roselle, Ill., said the teen-ager did not get through the full course of daily 500-milligram Levaquin pills.
“After five days, it was as if a bomb went off in her body,” said the sister. “She collapsed at school and had to be half-carried out of the building.”
Noto said her sister had been a talented musician, artist and athlete, advancing to within a few points of a black belt in Tae Kwon Do karate.
The girl, now 20, can walk only a short distance at a time, according to her sister. She attends college and gets around on an electric scooter.
She has had 29 orthopedic casts to prevent tendon rupture in her arms and legs, her sister said, and the hands that once played the piano and executed the swift movements of karate are often too weak to pick up a book.
More than 2,000 children with pneumonia or ear infections will be receiving Levaquin in trials being sponsored by Johnson & Johnson Pharmaceutical Research & Development Corp.
The ongoing pneumonia trials stopped recruiting subjects two weeks ago. Children age 6 months to 5 years are still being recruited for the otitis media, or ear infection, trial.
The purpose of that trial is to compare the effectiveness and safety of Levaquin with another antibiotic, Augmentin, according to information posted on a government Web site, clinicaltrials.gov.
Dr. Edward Goldblatt, an Alabaster, Ala., pediatrician, said he signed up to participate in the trial but withdrew because it required so much time. He said he hoped the trial succeeded, because “we need another antibiotic for this condition.”
“There are some antibiotic-resistant pneumonias and ear infections in children that can be most severe,” he said. “Some of them are resistant to just about anything we can give by mouth.”
Ortho-McNeil spokespersons said the company organized clinical trials of Levaquin for pediatrics use at the request of FDA.
They said that because of growing bacterial resistance to drugs, the agency is eager to increase the number of antibiotics available for use in children.
In addition to the warning that Levaquin has not been shown to be safe for children, the drug label states that experiments on immature animals of several species showed that it and other quinolones harmed cartilage and eroded weight-bearing joints.
Ortho-McNeil spokeswoman Leslie Fishman said concern that quinolones might hinder the growth of cartilage in children was based solely on these animal studies.
“There was concern at the outset, but there has never been a report of cartilage damage in a child,” she said. “Based on the available data, it (the early concern) did not pan out.”
She provided a paper published this year by scientists from Israel, Costa Rica and Switzerland, all of whom disclosed that they receive research funding from Johnson & Johnson or other pharmaceutical companies that produce quinolones.
The paper concluded that cartilage damage by quinolones “is a laboratory phenomenon in juvenile animals” and has not been documented in children who were given the drugs because of hard-to-treat infections.
FDA officials declined to answer questions on the record about the issue of quinolones and children. Speaking on background, an official said the agency faces a complicated decision in the matter.
The fact that laboratory studies show cartilage deformation in juveniles from several species, including rats, guinea pigs and dogs, rather than just one species that might have a unique susceptibility, is significant, the official said.
Also, doses used in these experiments were similar to levels that would be given to children.
On the other hand, with growing problems of bacterial resistance to antibiotics and the fact that a child might be allergic to another drug, the agency’s scientific advisers have urged it to establish safe quinolone levels as backup drugs for children.
Some doctors don’t believe anything should be done to weaken restraints on use of quinolones.
“I feel these drugs should be used only by specialists in infectious disease,” said Dr. Edward Cooper, a general practitioner who works at a walk-in clinic in San Jose, Calif.
Cooper said the drugs are commonly prescribed as first-line antibiotics when they should not be used in most cases unless other antibiotics have been shown not to work.
The problem is exacerbated, some doctors and researchers say, by errors in prescribing the drug in a climate unduly influenced by the high-pressure sales tactics of pharmaceutical manufacturers.
“The drug reps will come by and extol the virtues of the medications and we get mailings every two months about how good these medications are,” Cooper said. “But they rarely tell doctors about the side effects.”
“I feel that it is like a dysfunctional family where no one is allowed to talk about the father’s drinking problem despite all the evidence to the contrary,” he said.
Records that came to light last year in an employment discrimination lawsuit in Chicago depict a sales climate consistent with Cooper’s observations.
In the suit, lawyers for Ortho-McNeil successfully moved to suppress evidence about “the efficacy, appropriate medical use, potential side effects and/or cost of Levaquin.”
Minutes of a meeting held in June 2000 and entered as evidence in the trial describe sales representatives being exhorted to push Levaquin.
They were urged to increase their calls to hospital officials, take them to lunch and sponsor office Christmas parties, the minutes show.
They were told to refer to Augmentin (the drug against which Levaquin will be compared in the children’s ear infection trial) as a “horse pill” and use a large piece of hard candy as an illustration, according to the minutes.
A federal judge directed a jury to rule in favor of Ortho-McNeil in the job discrimination matter and the plaintiff has appealed. Ortho-McNeil spokesman Fishman said the company could not comment about ongoing litigation.
In 1996, Ralph Nader’s Public Citizen consumer advocate organization petitioned the FDA to require that quinolone labels contain warnings about tendon rupture, a step cautious European regulators already had taken.
Public Citizen requested that the warnings be printed in boldface type and that the agency send a “Dear Doctor” letter to all physicians, specifically calling their attention to the danger.
The FDA required the warnings — on page 15 of the 35-page label and not in boldface type — but did not send the letter.
Larry Sasich, a Public Citizen pharmacist who signed the petition, said this was disappointing.
“We thought it was necessary to raise a red flag,” said Sasich, “because who would suspect that you would get tendon rupture from an antibiotic?”
He said doctors seldom have time to read lengthy drug “labels.”
In fact, researchers at the University of Pennsylvania School of Medicine last year analyzed 100 quinolone prescriptions written in a hospital emergency room and found that only one of them was written for the right condition and in the right dosage.
Dr. Ebbing Lautenbach, an epidemiologist, said in an interview that he and the other researchers were primarily concerned not with adverse reactions but by worries that overuse of quinolones would accelerate the development of quinolone-resistant germs.
He said that after analyzing a random prescription for the antibiotic and the 99 subsequent prescriptions for the same quinolone, they found:
In 43 cases, another drug was considered the proper first-line treatment.
In 27, there was no documentation of infection.
In 11, there was no way to assess the need for antibiotics.
In the remaining 19 cases, quinolones were found to have been the correct medication, but only one of these patients received the correct dose for the correct duration.
No one knows how many Americans experience adverse reactions to quinolones each year. The FDA estimates that between one and 10 percent of all adverse drug reactions are reported to its Adverse Events Reporting System.
They say the system is intended to help them spot trends in drug side effects and is not a comprehensive accounting of drug reactions.
Because of the Internet, persons who believe they have been harmed by quinolone side effects are becoming more and more visible. Bound together by Web sites on which they share stories, they have formed a bitter electronic community.
Flockhart is skeptical about some of the self-reported reactions. Such people may have some other problem and until they are examined by a physician trained in clinical pharmacology, no one will know what they have, he says.
Others, he also believes, have quinolone reactions that are misdiagnosed as something else.
“Quinolones are really the tip of the iceberg,” he said. “It’s the general fact that we’re not good at recognizing and treating adverse drug reactions in primary care.”
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