Tag Archives: black box warning

Dr. Bennett identifies what the government should be doing — but isn’t — to guard against unsafe prescription drugs

Dr. Charles Bennett has been an advocate for addressing fluoroquinolone safety concerns for many years. He has has filed multiple petitions with the FDA to get them to change the warning labels for fluoroquinolones–one of the petitions is to get the FDA to add Psychiatric Adverse Events to the Levaquin/levofloxacin warning label, another is to have the FDA add “Possible Mitochondrial Toxicity” to the Levaquin Label, another requesting a black box warning to specifically identify psychiatric adverse events, including suicide and suicide-related adverse events, and likely others. These petitions have led to warning label changes, and have been featured in many of the news stories about fluoroquinolones. Dr. Bennett has also testified before the FDA about fluoroquinolone adverse reactions, and has helped many “floxies” to gain information and support. He is a wonderful advocate, and his advocacy work has increased the credibility of other advocates for fluoroquinolone toxicity awareness. He has changed how many people think of fluoroquinolones, and he has changed how fluoroquinolones are prescribed. He is making a difference.

Dr. Bennett recently wrote a wonderful editorial that was published in the LA Times entitled, “What the government should be doing — but isn’t — to guard against unsafe prescription drugs.” I highly recommend that you read and share it. He has some great ideas and insights, some of which I’m going to highlight in this post (all italicized and indented sections of this post are quotes from the editorial).

He, and his co-authors, state:

The failings are at every point in the system, starting with drug approvals. But we believe there is a particularly serious problem with the mechanisms for identifying, monitoring and disseminating information about issues with a drug after its release.

Once a drug is approved for market, the FDA relies on an informal and ineffective system of case reports and citizens’ petitions to alert it to problems and adverse events. In the past, case reports, submitted to medical journals by physicians, served as an important mechanism for detailing drug toxicity. But today, because of changes to editorial guidelines, peer-reviewed journals rarely accept such reports for publication.

Indeed. Take it from a doctor who specializes in studying adverse drug reactions that the current system of tracking and addressing concerns about adverse drug reactions is failing and ineffective. How many of the thousands (perhaps millions) of adverse reactions to fluoroquinolones have been reported to the FDA through either the adverse event reporting system, a case report, or a citizen’s petition? Unfortunately, not many. It should be noted that, “Many studies have documented that only 10%-15% of serious adverse reactions are reported” to the FDA. Though I encourage every “floxie” to report his or her adverse reaction to the FDA, a voluntary reporting system that is confusing and difficult to navigate, is not a particularly effective way of tracking the actual incidence of adverse drug reactions.

Dr. Bennett also notes that Citizen’s Petitions (many of which he has filed) are not an effective tool for tracking and evaluating post-market adverse drug reactions:

Citizens’ petitions, in which any citizen can petition the FDA to report adverse drug effects, are intended to be another check. But the petition process is cumbersome, and they are rarely granted. Of the 1,915 Citizens Petitions filed in the 12-year period between 2001 and 2013, a total of 13 were granted. Many go unanswered altogether.

The citizen’s petitions filed by Dr. Bennett, Public Citizen, and others, have been helpful advocacy tools, but, as Dr. Bennett and his co-authors point out, they have not been adequate.

Rather than continuing with the ineffective system of depending on patient and doctor reports of adverse reactions, citizen’s petitions, and case-reports to monitor and track adverse drug reactions, Dr. Bennett suggests that a new system for tracking and monitoring drugs with black-box warnings be implemented.

We propose a “black box” database or “registry,” publicly available and simple to use, that would contain extensive information about where, by whom and for what purpose black box drugs are prescribed, as well as where and in what quantities such drugs are being distributed and sold. Information about adverse side effects, culled from the myriad of government databases that now collect them, would also be consolidated in an open form and format.

In addition to the benefits of a black box database/registry noted above, a black box database/registry also has the potential to decrease usage of drugs that have black box warnings:

Is there a chance that the existence of a black box registry would decrease the use of those drugs? Possibly, and that would be a good thing. Too often black box warnings are seen as meaningless, and they are counteracted with marketing campaigns that promote off-label use. If adding more transparency, thought and effort to the prescription and sale of dangerous drugs winds up decreasing their use, that will likely be a beneficial side effect.

It would be WONDERFUL if there were a system in-place that cut down on unnecessary fluoroquinolone prescriptions. It would be WONDERFUL if there were a system in-place that adequately communicated the real risks of fluoroquinolones. I think that Dr. Bennett’s idea of creating a black box registry is an excellent way to do both those things, and it’s absolutely worth a try. The system that we currently have for tracking and addressing adverse drug reactions is woefully inadequate. Change is good – especially if it is in the direction of making people safer.

Thank you Dr. Bennett and co-authors for writing “What the government should be doing — but isn’t — to guard against unsafe prescription drugs.” Your insights and advocacy are greatly appreciated!

*****

Children are Being Hurt By Fluoroquinolone Antibiotics

It breaks my heart when I hear about children getting “floxed.” It’s bad enough that fluoroquinolones inflict pain, tendon tears and ruptures, dysglycemia, insomnia, psychiatric problems, autonomic nervous system disturbances, hormonal issues, and more, on adults–it’s horrifying when those things happen to children. Our children, our babies, our innocent and precious kids, are getting hurt by fluoroquinolones too. We try to protect our children–it’s our job to protect them. We trust that when we go to the pediatrician, he or she won’t poison our babies, but, tragically, sometimes pediatricians do, indeed, poison children with fluoroquinolones. Sometimes they prescribe Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin, and Floxin/ofloxacin to children, and sometimes those children suffer devastating consequences from taking those drugs.

It is so incredibly wrong to give children drugs that can cause permanent pain and disability that I’m furious that it happens at all. I’m also furious that there aren’t any consequences for the various parties that allow fluoroquinolones to be prescribed to children. In case it needs to be said, hurting children, and chemically causing pain and disability for young boys and girls, is wrong.

It is well-documented that fluoroquinolones cause permanent lameness in juvenile animals and that they are contraindicated for the pediatric population. A review in U.S. Pharmacist notes that:

“Fluoroquinolones have demonstrated adverse effects on cartilage development in juvenile animals through the inflammation and destruction of weight-bearing joints.  These arthropathies were often irreversible, and their potential occurrence in children limited the use of fluoroquinolones in this population.  In one pediatric study, ciprofloxacin had a 3.3% (9.3% vs. 6.0%) absolute risk increase in musculoskeletal events within 6 weeks of treatment compared with control agents used to treat complicated UTIs or pyelonephritis. Adefurin and colleagues found a 57% increased relative risk of arthropathy in children given ciprofloxacin (21% overall) versus those in a non-fluoroquinolone comparator arm. In contrast to animal models, neither dose nor duration had an effect on the rate or severity of arthropathy.  A 2007 study by Noel and colleagues determined the incidence of musculoskeletal events (primarily arthralgias) to be greater in children treated with levofloxacin compared with nonfluoroquinolone-treated children at 2 months (2.1% vs. 0.9%; P = .04) and 12 months (3.4% vs. 1.8%; P = .03).  These results and the severity of the effects should be weighed heavily when initiation of fluoroquinolones is being contemplated in pediatric patients.”

To summarize, fluoroquinolones can cause irreversible musculoskeletal harm and in doing so, they can put an end to a child’s days of running, jumping, playing soccer, skiing, dancing, etc. Think about that for a second–a drug, an antibiotic no less, can cause permanent damage to the musculoskeletal system of a child. Fluoroquinolones also have serious CNS effects, and can cause psychiatric disturbances as well as loss of memory and concentration. Children, with their developing bodies and minds, should not be subjected to dangerous, disabling drugs that can set back their development and their lives.

Given the documented adverse effects of fluoroquinolones on children, and the black box warning that notes that they can cause disability, the following examples of children being hurt by fluoroquinolones are both infuriating and heartbreaking. Still, I think they should be shared, so as to warn other parents of the dangers of these drugs, and hopefully fewer children will get floxed in the future.

I have paraphrased the stories that I’ve heard, but all of these are true:

  1. A 16 year old boy has Cipro 17 times over the last 7 years. He has various health issues, including a problem with the bones in his feet. The pain in his feet is so bad that he has had to stop school and homeschool on the computer.
  2. A 9 year old took fluoroquinolone ear drops twice as a toddler and suffers with chronic foot and knee pain.
  3. A young woman was floxed 4 1/2 years ago at 16 years old. After about 2 years, she got better, eventually reaching about 90-95% better, only to have a relapse for no apparent reason about a year later (which is where we are now)! She has had MANY devastating side effects, and still cannot work. When she got her first job is when the relapse took place.
  4. A 15 year old girl passed away 6 days after her 10 day Levaquin script.
  5. An 8 year old girl had to quit all sports swimming and gymnastics. She is now going to school but no P.E., and no Dr. Wants to take responsibility for how to help with her pain. It’s been only 2 weeks since taking 3 days worth and then being hospitalized because of the effects.
  6. A 10 year old girl who cannot stand or walk, and no doctors believe her. 
  7. A 16 year old girl took 2 pills of 500 mg of cipro and now has nerve twitching, leg pain, anxiety, and a whole bunch of other symptoms. 

These are kids! They are children and adolescents who are being hurt by fluoroquinolones. They are suffering and there is nothing that doctors can do to relieve their pain. It’s beyond heartbreaking–it’s infuriating–and it needs to stop. The FDA needs to put enforceable restrictions on pediatric fluoroquinolone use. The doctors who prescribe fluoroquinolones to children need to be held accountable when they hurt children with fluoroquinolones (either through Medical Board punishment, or lawsuits). The pharmaceutical companies that make these dangerous drugs need to be punished and they need to compensate their victims. Researchers need to be looking into a cure for fluoroquinolone toxicity. All parties involved need to help these kids to recover, because there really isn’t anything okay about hurting a child.

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Updated Black-box Warnings for Fluoroquinolones

In July, 2016, the FDA made significant changes to the warning labels for all fluoroquinolone antibiotics (Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin, Floxin/ofloxacin, Noroxin/norfloxacin, and Factive/gemifloxacin). These label changes include black-box warnings for fluoroquinolones that state:

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

  • Fluoroquinolones, including CIPRO®, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together including:
    • Tendinitis and tendon rupture 
    • Peripheral neuropathy
    • Central nervous system effects
  • Discontinue CIPRO immediately and avoid the use of fluoroquinolones, including CIPRO, in patients who experience any of these serious adverse reactions. Fluoroquinolones, including CIPRO, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid CIPRO in patients with known history of myasthenia gravis.
  • Because fluoroquinolones, including CIPRO, have been associated with serious adverse reactions, reserve CIPRO for use in patients who have no alternative treatment options for the following indications:
    • Acute exacerbation of chronic bronchitis
    • Acute uncomplicated cystitis
    • Acute sinusitis

You can view all of the updated fluoroquinolone labels HERE.

These updated black-box warning labels are HUGE steps in the right direction. The FDA is acknowledging, in a highlighted black-box section of the warning labels, that fluoroquinolone adverse-effects can be serious, irreversible, and disabling. They’re also acknowledging peripheral neuropathy and central nervous system effects, in addition to the adverse-effects on tendons, in the black-box warning. Additionally, the black-box warning states explicitly that fluoroquinolones should not be used for treatment of patients with chronic bronchitis, uncomplicated cystitis (I wish they would have said “urinary tract infections” instead of “cystitis” as they did in the hearings and preliminary documentation), and sinusitis, unless there are no alternative treatment options.

If this updated black-box warning had been in place when fluoroquinolones were first introduced to the market (in the 1980s and 1990s), many people would have been saved from being “floxed.” If these warnings had been in place when fluoroquinolones entered the market, or even when people started screaming about the significant damages and injuries caused by fluoroquinolones, perhaps more doctors would be aware of the dangers of these drugs, and they would be used more appropriately (only in life-or-death situations where there are no alternatives available). Currently, unfortunately, most people are not aware of the devastating effects of fluoroquinolones. Hopefully this updated black-box warning label will enlighten both patients and physicians about the serious and severe dangers of fluoroquinolones.

Prior to this update, the black-box warning for Cipro (and other fluoroquinolones) stated:

Fluoroquinolones, including CIPRO®, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (see WARNINGS).

Fluoroquinolones, including CIPRO, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid CIPRO in patients with known history of myasthenia gravis (see WARNINGS).

This 2008 black-box warning was hard fought for, as both Bayer and Ortho-McNeil-Janssen (a subsidiary of Johnson & Johnson) wanted to bury the risks of tendon ruptures in small-text embedded in the warning labels, rather than highlighting the increased risk in a black-box warning. It was only after Public Citizen sued the FDA that this black-box warning was added to fluoroquinolone warning labels.

Though the old black-box warning was a significant victory at the time, it left much to be desired. The statement that, “This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants,” suggests that those who are under 60 years of age, not taking corticosteroid drugs, and who have not had kidney, heart, or lung transplants, can safely take fluoroquinolones. Though it is also noted that the risk of tendon ruptures is increased for people of “all ages,” it is common to hear of people being told that they wouldn’t have problems with fluoroquinolones because only older people, or people with myasthenia gravis, are at risk for experiencing adverse-effects. This simply isn’t true, as there are thousands of people who have been hurt by fluoroquinolones who are under the age of 60, do not have myasthenia gravis, who are not on corticosteroid drugs, and who have not had an organ transplant.

The old black-box warning gave people (both patients and physicians alike) the impression that fluoroquinolones are only unsafe for certain, small sections of the population. The truth is, fluoroquinolones can cause devastating, severe, disabling adverse-reactions in people who are young and old, strong and weak, fit and out-of-shape, and, at this time, there is no way to determine who will have an adverse-reaction and who won’t. There are almost certainly factors that predispose some people toward having devastating adverse-reactions to fluoroquinolones while others seem to be able to take fluoroquinolones without problem, but we don’t know what those predispositions are. No one knows if people who have latent autoimmune or endocrine system disorders, or who have MTHFR genetic mutations, or who are G6PD deficient, or who have leaky gut, or who have been exposed to heavy metals, or any other potential risk factor, are more succeptible to fluoroquinolone adverse-reactions than anyone else. There is a dice-roll, a pull of the Russian roulette trigger, every time ANYONE takes a fluoroquinolone because NO ONE knows what the real risk factors are, or even how frequent/rare adverse-reactions are. I wish that it was explicitly said on the fluoroquinolone warning labels, preferably in the black-box warning, that risk-factors are currently unknown and that everyone who takes fluoroquinolones is potentially at risk for experiencing disabling adverse-effects.

I also wish that it was noted in the black-box warning that adverse reactions to fluoroquinolones can be delayed for weeks, months, or even years after administration of the drugs has ceased. And I wish that people were warned that ceasing administration of the drug may not stop the adverse-reaction, and that the symptoms of fluoroquinolone toxicity can continue long after the drug “should” be out of one’s system.

I also wish that the danger of co-administering fluoroquinolones and corticosteroid drugs had stayed in the black-box warning, and I wish that the contraindication of NSAIDs and fluoroquinolones was noted in the black-box warning.

I wish that “cystitis” was changed to “urinary tract infection,” or that they were both mentioned as ailments for which the use of fluoroquinolones is not appropriate unless there is no alternative. I also wish that prostatitis and travelers’ diarrhea were added to the list of ailments for which fluoroquinolones should not be used unless there is no alternative.

Perhaps the next iteration of the black-box warning on fluoroquinolones will note those things. I wish I, and my doctor, had been warned more thoroughly about the dangers of fluoroquinolones before she prescribed them to me, and before I took them. Hopefully the updated black-box warning label will help physicians and patients to realize how dangerous fluoroquinolones are, and will keep many people from getting “floxed.”

Though the updated black-box warnings still leave a bit to be desired, they are a HUGE step in the right direction. Acknowledgement from the FDA that fluoroquinolone adverse-effects can be irreversible and disabling, and that they should not be used to treat many common conditions unless there are no other treatment options available, is very big news, and it should be celebrated. We are making progress, and hopefully fewer people will be hurt by fluoroquinolones because of these black-box warning updates.

 

 

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