Rx warning: possible mitochondrial toxicity
By J. Ryne Danielson
Powerful antibiotics Levaquin and Cipro, as well as other members of the flouroquinolone family, may be responsible for dangerous but unacknowledged side effects, including mitochondrial toxicity syndrome, a disruption of cellular function which causes severe nerve damage. photo by Sarah Pack, Public Relations
When Raja Fayad, M.D., was murdered on the campus of the University of South Carolina this past February, he was working on something big, something Charles Bennett, M.D., Ph.D., hopes will be part of his legacy.
Bennett is the SmartState endowed chair for medication safety and efficacy at the South Carolina College of Pharmacy, a partnership between USC and MUSC. Bennett also runs one of the largest and most successful pharmaceutical watchdog groups in the country, the Southern Network on Adverse Reactions — SONAR.
In June and September 2014, SONAR filed two citizen petitions with the Food and Drug Administration regarding fluoroquinolones, a class of drug that includes the powerful antibiotics levofloxacin and ciprofloxacin — Levaquin and Cipro. Bennett wants “possible mitochondrial toxicity” and “serious psychiatric events” added to the drugs’ black box labels — the most prominent warning label required by the FDA.
SONAR has gathered testimony from hundreds of patients who have experienced muscle weakness, chronic fatigue, cardiomyopathy, hearing loss, developmental disorders, severe depression or nerve damage after taking Levaquin and related drugs.
A recent report from the FDA’s Office of Safety and Epidemiology has also linked neurodegenerative diseases like Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis (ALS) to quinolones and the mitochondrial toxicity reported by some patients after taking them.
The problem: most patients – even most doctors – don’t know these side effects exist. On top of that, the most common use of the drugs is off-label, that is, for uses other than those explicitly approved by the FDA.
|Dr. Charlest Bennett is the SmartState endowed chair for medication safety and efficacy at the South Carolina College of Pharmacy.
Bennett gave an example: “A patient goes to see their doctor on a Friday afternoon because they don’t feel well. What we should do is watch that patient closely, see if they really have an infection; they probably don’t. The patient hates that. On the other hand, give them a prescription for Levaquin and they think, ‘my doctor’s taking good care of me.’”
The drugs are often prescribed, Bennett said, to placate patients — and doctors themselves.
“The antibiotics are viewed as harmless and effective,” Bennett said. “So, why not write the prescription?”
But, he stressed, the risk-benefit profile of quionolones, like all medications, is favorable only when the drugs are administered according to FDA–approved indications.
Pharmaceutical companies are not allowed to market their drugs off–label, but doctors are allowed to prescribe drugs, including quinolones, for off–label use. Seventy–five percent of all prescriptions are written off-label, Bennett said. This presents problems when doctors are not fully aware of the possible side effects associated with the drugs they are prescribing, which is why Bennett believes getting a black box warning is so important.
Bennett is clear: He doesn’t want the drugs banned. Levaquin and Cipro are important drugs, especially in clinical oncology where they are used to treat infections in patients undergoing chemotherapy.
“Every drug has side effects,”Bennett said. “If the drug has a favorable risk-benefit profile, then it should be on the market.”
For mitochondrial toxicity syndrome, Bennett believes, the risk could be mitigated with a simple genetic test. But, before this test can be developed, the risks must be acknowledged.
SONAR is the only pharmaceutical watchdog group that focuses on drugs used in the treatment of cancer.
“We have a niche that nobody else in the country can be in,” Bennett said. “The science is too hard. You have to understand oncology.”
Bennett does. He is an oncologist. It is this clinical training that sets him apart in his field. Being a clinician, focusing on pharmaceutical safety, he believes, is very different from being a statistician, looking for safety signals. Rather than combing large databases for adverse drug reactions, like most watchdogs, Bennett goes directly to the patients themselves.
SONAR is a fitting acronym for Bennett’s group. “SONAR listens to people who have been harmed by an adverse drug reaction,” he said. “We give patients a voice.” He continued, “If a patient takes a drug and experiences a terrible side effect, what could they do? What could they do? They’d be upset, I know that. But, what could an ordinary citizen do?
“One option might be to call their doctor. What would the doctor say? ‘That’s a terrible thing that’s happened to you, I’ll put it in your notes.’ The patient wouldn’t feel very good about that.
“So, they’d say, ‘Let me call the FDA,’ and they’ll call up some number in Washington. They’re put through a series of push-ones and push-twos, until they get to a person that says, ‘That’s a terrible thing that’s happened to you, please send us a two-page report.’
“The FDA gets more than 250,000 such reports every year. The patient would be filed away and never even get a thank-you note.
“Then the patient might call the drug company. One can imagine how that would go. The drug company will have a drug safety representative who is required to file a report with the FDA within 15 days. They’ll say, ‘That’s a terrible thing,’ and file their report. But, at the end of the day, the patient is back at square one.
“A final option,” Bennett said, “is SONAR.”
Bennett’s group has personally collected hundreds of patients’ stories from across the country, in addition to the more than 130,000 adverse event reports for quinolones that have been filed with the FDA.
“Levaquin, Cipro — these are billion–dollar drugs,” Bennett said. “But the FDA has the authority and responsibility to ensure they’re labeled correctly.”
Dr. Raja Fayad, killed last February in a shooting on USC’s Columbia campus, was working to prove a link between Levaquin and and MTS. His paper is still under review. photo provided
Before Fayad was killed, he was engaged in documenting these side effects in a preclinical setting, adding empirical evidence to a surfeit of anecdotal accounts. Fayad’s paper, submitted last summer, has been under review for eight months. This is an unusually long time, Bennett said, saying it amounted to a “pocket veto.” Since Fayad is no longer able to fight for his work, Bennett is stepping in.
“I spoke with the editor and said I need this paper adjudicated – it’s an important piece of Raja’s legacy,” Bennett explained. “I received a commitment that the adjudication will happen.”
Bennett said the pushback from drug companies has been “unbelievable.”
The companies he has taken on have a market capitalization in excess of $700 trillion; their products are worth hundreds of billions of dollars.
“You can’t do what I do and think the drug companies don’t notice you,” he said. “Wyeth, Celegene, Eli Lilly, Novartis, Roche, Genentech, even General Electric — you can’t find a major drug company that SONAR hasn’t found an issue with.”
Bennett’s work with erythropoietin and darbepeotin, to cite one example, led to a 90 percent decrease in annual sales of these drugs in the cancer setting – from $6 billion to less than $1 billion.
Bennett said many things can happen when one finds themselves on the wrong end of a powerful corporation: “Sometimes you find that you’re not invited to conferences you used to be invited to. You’re kicked off committees. Sometimes they send private investigators after you.
“They’ve looked at everything I’ve ever done in my life,” Bennett said. “At the end of the day, most people would not do my work. It’s far too dangerous.”
Bennett’s grants have been repeatedly and aggressively audited. “I am pleased that after careful review,” he said, “they did not identify a single dollar that I had misspent over a 27 year academic career. There has been a concerted effort to shut my program down, but it is not shut down. We will be heard.”
Pushback doesn’t just come from drug companies, Bennett said, but from the FDA itself. After filing a Freedom of Information Act request with the FDA, Bennett discovered the agency’s own safety experts had investigated reports related to fluoroquinolones and found evidence of the same side effects SONAR found.
SONAR’s citizen petitions request that the FDA include its own safety panel’s findings in the drugs’ package inserts. The FDA has indicated they have received the citizen petitions, and they are under review, but no action has been taken to date.
“The FDA is not in the business of pushing back very hard against the drug companies,” Bennett said. “The FDA’s client is the pharmaceutical industry.”
Bennett explained: “If you’re an underpaid government employee, working at the FDA — you maybe have a good heart — but if you decide you want a better paying job, what do you do? You take a job with the pharmaceutical industry. If your resume shows you’ve been leading the charge to remove drugs from the market, the only place that resume is going is in the garbage.”
Bennett said the current method for determining the severity and rarity of side effects in off–label uses of medications is unacceptable. For one, he said, it is very expensive to get a drug approved for a specific use. This is why so many prescriptions are written off–label to begin with. “It costs about $800 million to do the appropriate testing to support a new indication for a drug. Many drug companies say, ‘Look, we’ve got a small number of labeled indications that we can live with — we’ll let the market take care of the rest.’”
How could a drug be around for 20 years and these side effects remain undocumented? Bennett said this failure reveals “not just a chip in the armor — the armor has fallen off. And this is not the only drug like this — I’ve investigated 50 drugs like this.”
Over the past few months, Bennett has met with 10 U.S. Senators and two Congressmen, including Republican Senators Tim Scott and Lindsey Graham of South Carolina and Democratic Congressman James Clyburn, who represents South Carolina’s 6th Congressional District. He has also made numerous media appearances in support of his petition.
But, Bennett stressed, he is not an advocate. He is a scientist.
“Scientists need a seat at the table,” Bennett said. “And so do these patients. They need a voice.”
Bennett said he is proud that MUSC and USC have stood by his controversial work and that this work has helped save so many lives. He is pleased that the NIH and the American Cancer Society have long supported his drug safety research. NIH continues to fund the work with a five year R01 grant — of which Bennett is the principal investigator. The American Cancer Society has also awarded Bennett a four-year
Institutional Research Grant that facilitates start–up funding for junior cancer researchers on the MUSC and USC campuses.
Most importantly, Bennett said, he is committed to helping disseminate Fayad’s work, which “will have important public health benefits for thousands.”
“In my life,” he said, “I always wanted to be in a position to make a difference and to save lives through public health and public policy initiatives. I think that’s what I am doing. SONAR has saved tens of thousands of lives and billions of dollars. That’s a good day’s work.”
April 2, 2015