Tag Archives: levofloxacin

Levaquin Production Stopped by J&J/Janssen Pharmaceuticals

Janssen Pharmaceuticals, part of Johnson & Johnson, has stopped production of (brand-name) Levaquin, according to the article, “Drug maker stopped making popular antibiotic Levaquin amid concerns about mental health side effects” published on the Indianapolis ABC affiliate RTV6 The Indy Channel. Janssen/J&J stopped producing both oral and IV Levaquin in December, 2017. The discontinuation of Levaquin production was confirmed by a Janssen/J&J spokesperson who stated, “The decision to discontinue LEVAQUIN was made due to the wide availability of alternative treatment options, and our focus on developing innovative medicines designed to address unmet medical patient needs.” Though that statement is BS propaganda, it is a direct confirmation from a Janssen Pharmaceuticals spokesperson that JANSSEN/JOHNSON & JOHNSON HAS DISCONTINUED PRODUCTION OF LEVAQUIN.

THIS IS REALLY BIG NEWS! IT’S HUGE! WHOA!

LEVAQUIN HAS BEEN REMOVED FROM THE MARKET!

Unfortunately, there is still plenty of levofloxacin (generic Levaquin, made by hundreds or thousands of generic pharmaceutical producers) on the market, and it is maiming (and killing) thousands of people each year. The fight against these drugs is far from over.

Still, the removal of brand-name LEVAQUIN from the market is a really big deal, and it’s something that we, as a community, should celebrate.

We did this. All the people who filed complaints with the FDA, who testified before the FDA, EMA, and other regulatory agencies, who reached out to the press and told their stories, who shared their story of pain and suffering brought on by fluoroquinolones, all the people who shared articles about fluoroquinolone toxicity, all the scientists who did research showing the harm done by fluoroquinolones, all the advocates, all the people in the floxie community, and all the people who listened–we did this! We screamed loudly enough that people listened. Our efforts made a difference, and Janssen Pharmaceuticals has stopped making Levaquin.

“Never doubt that a small group of committed people can change the world. Indeed it is the only thing that ever has.”—Margaret Mead

I never thought that one of the pharmaceutical giants that has made billions from fluroquinolones would stop making them. Janssen Pharmaceuticals and J&J are huge–they are behemoths–and I never thought that we could move or effect them. But we did.

The efforts of everyone in the “floxie” community contributed to this outcome. We–you–should be proud.

That is my optimistic take on things. We all have an optimistic side. We all have a pessimistic side too, and here’s the bad news.

Janssen decided to stop making Levaquin because, a) their market share was small because generic levofloxacin is cheaper and widely available (“’Levaquin was only about 1 percent of the market share, and 99 percent was the generic,’ said Bennett.”), and b) they were facing significant lawsuits, and to avoid liability for the drugs they created, they pulled them from the market.

Victims of pharmaceuticals can’t sue drug-makers for harming them, they can only sue for “failure to warn” of the dangers of the drugs. This is ridiculous – I can sue you for hitting me in the face with a sledgehammer even if you warn me that you’re going to do it and that it’s going to hurt – but pharmaceutical companies aren’t held to the same standards as you or me. It’s assumed that their deadly products are mainly good and that warning of the potential for bad effects is sufficient to wash their hands of liability and responsibility. On top of that, they don’t even have to directly warn YOU, they only have to say that they warned your doctor, the “learned intermediary” of the dangers of the drugs (or, at least they have to in theory – it’s assumed that doctors actually know what’s on the warning labels for pharmaceuticals… but most don’t). Both the “failure to warn” notion and the “learned intermediary” notions are crap, and I hate them, but they’re how the system is set up.

Because victims of pharmaceuticals can only sue for “failure to warn” the door for them to sue is only open when the drug warning labels change. Fluoroquinolone warning labels have undergone significant changes in recent years. In reverse-chronological order, the following warning label changes have been added to fluoroquinolone labels:

  • In July, 2018, fluoroquinolone warning labels were changed to note that, “Fluoroquinolone Antibiotics: FDA Requires Labeling Changes Due to Low Blood Sugar Levels and Mental Health Side Effects” – Drug Safety Communication
  • In July, 2016, fluoroquinolone warning labels were changed to note that, “FDA Drug Safety Communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together” – Drug Safety Communication
  • In May, 2016, fluoroquinolone warning labels were changed to note that, “FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects” – Drug Safety Communication
  • In August, 2013, fluoroquinolone warning labels were changed to note that, “FDA Drug Safety Communication: FDA requires label changes to warn of risk for possibly permanent nerve damage from antibacterial fluoroquinolone drugs taken by mouth or by injection” – Drug Safety Communication
  • In July, 2008, fluoroquinolone warning labels were changed to note that, “FDA is notifying the makers of fluoroquinolone antimicrobial drugs for systemic use of the need to add a boxed warning to the prescribing information about the increased risk of developing tendinitis and tendon rupture in patients taking fluoroquinolones and to develop a Medication Guide for patients.” – Drug Safety Communication

With each of these warning label changes, the door opened for people to sue Janssen and Johnson & Johnson for the harm that Levaquin did to them. (It should be noted that each of these warning labels changed because of advocacy done by the “floxie” community. We screamed, and, slowly, the FDA listened.) Some people did successfully sue the drug companies that hurt them–they gained some compensation and justice.

Perhaps it’s cynical, but it certainly seems more logical than the BS explanation the Janssen spokesperson gave (noted above) that the reason that Janssen Pharmaceuticals took Levaquin off the market was because they didn’t want to be held liable for the blood sugar level changes and the mental health side-effects of Levaquin. They weren’t making much money off it anyhow (because of generics taking the bulk of the market share), this warning label update opened up a new load of liability, and they did a cost-benefit analysis that led them to take it off the market.

All’s well that ends well, and they took Levaquin off the market, and that’s a good thing, right? Well, it’s more complicated than that.

Because of a stupid and asinine rule put in place by the FDA and a lousy decision of the Supreme Court, victims of generic pharmaceuticals cannot sue generic pharmaceutical manufacturers. It all goes back to the “failure to warn” rules noted above. The FDA says that only brand-name drug manufacturers can change drug warning labels, and since generic drug manufacturers can’t change the warning labels, they cannot be held responsible for what’s on the warning labels. This results in victims of generic drugs being unable to hold anyone responsible for the harm done to them by the drugs. There have been a couple cases where brand-name drug companies were held responsible for the harm done by generic drugs, but the precedent wasn’t set very solidly, and most attorneys in most states still aren’t taking cases of people who have been hurt by generic pharmaceuticals. Still, I think that Janssen and J&J saw the writing on the wall–that they could potentially be held responsible for all the Levaquin and levofloxacin-induced mental health side effects, permanently disabling side effects, permanent peripheral neuropathy, tendon tears, and more. So, they hedged their bets. Their legal team, I’m betting, will now argue that they can’t be held responsible for the harm done by levofloxacin because they don’t even make Levaquin any more, and how can they be held responsible for a product that they don’t even produce? My reply is that they can, and should, be held responsible for the drug that THEY CREATED. Johnson & Johnson created and held the patent on Levaquin for a long time. They made billions of dollars off of it. They can, and should, be held responsible for the effects of their creation. The generic drug companies should also be held responsible for the harm that their drugs do, and the FDA should be held responsible for their warning labels (and failure to warn the public about these incredibly dangerous drugs).

We pushed the FDA to change their warning labels. They did, and we should be proud of that. The warning label changes scared Janssen and J&J enough that they stopped production of Levaquin, and we should be proud of that too.

We should also be diligent about the consequences of the removal of Levaquin from the market, and we should continue to work for change in the legal/justice system so that it leans more toward justice for victims, and less toward corporate protection. It is horridly difficult for victims of pharmaceuticals to gain justice or compensation through the legal system as it is currently set up. Janssen pharmaceuticals just made a move to make it even more difficult for victims of Levaquin and levofloxacin to gain justice.

Know what they’re doing. Stay on top of them. Celebrate our victories, then come back to the battlefield fighting. As long as millions of prescriptions of levofloxacin are distributed each year, and thousands of people are maimed by the drugs, our fight isn’t over.

Can Floxies Drink Alcohol?

Many people have asked me if they can/should drink alcohol post-flox.

As with most things, the answer is – it depends, and everyone is different.

Some Floxies tolerate alcohol fine, while others don’t.

Alcohol is, of course, bad for you. It’s hard on the liver, and can lead to cirrhosis and alcoholic hepatitis. It burdens your liver’s detoxification abilities and hinders your ability to get rid of other toxins. Alcohol wreaks havoc on the gut microbiome, and can encourage candida growth. Alcohol weakens the immune system, and can make you more succeptible to other illnesses. I could go on and on because there are hundreds of articles about the harm that alcohol inflicts on the human body. No matter how many videos come out about tequila being a probiotic, or articles there are about wine containing resveritrol, alcohol is not a health elixir. It is not good for you.

HOWEVER, it is quite fun (IMO), and it even has some health benefits–it’s a painkiller and it reduces feelings of stress and anxiety. Alcohol has enough redeeming qualities that billions of people around the world, most of whom are aware of the negative effects of alcohol, consume it. I do, and so do many other floxies.

When I first got floxed, I stopped drinking for a while. My body was going hay-wire in every conceivable way, and I didn’t want to contribute to my problems by knowingly consuming a substance that is bad for me. I think that abstaining from alcohol during the acute phase of fluoroquinolone toxicity was the right thing for me to do.

Once my body stabilized (i.e. it stopped feeling like a bomb was going off in my body, and I even had some improved/normal days) I started having a drink every once in a while. Even though I could drink, I found that my tolerance for alcohol was greatly diminished. Before I got floxed I could handle three-ish drinks in an evening (and I thoroughly enjoyed drinking them). After getting floxed, my tolerance was one drink a night (that was barely enjoyable). I didn’t even want to drink more than that–I struggle to explain why, but I just felt done after 3/4 of a drink. Over time (I am now a bit over 5 years post-flox) my tolerance increased, and I can now comfortably have two alcoholic beverages in an evening. That’s plenty for me, in my personal opinion of how much I should/shouldn’t drink.

I never experienced a relapse in fluoroquinolone toxicity symptoms as a direct result of drinking alcohol, but other people have, and I encourage everyone who wants to drink post-flox to be very careful and cautious with alcohol consumption. Comments such as this one, from Bob (and the comment just above it when you click on the link, from Ann), are examples of alcohol triggering an increase in, or relapse of, fluoroquinolone toxicity symptoms:

After getting floxed I had relapses to alcohol which I only drank on vacation. I suspect this is due to severe kill off of gut flora. I am afraid to drink anymore.

This comment from Mark also notes that alcohol consumption can lead to fluoroquinolone toxicity symptom flares:

I cheated this weekend and drank alcohol/ate dairy. You know what? It flared up my cipro symptoms full force. Knee joints started cracking like crazy, achilles heal flare, etc. I’m convinced that we are all suffering an overgrowth of yeast and the faster we can get that under control, the healthier we will be.

Some people have a more moderate reaction to alcohol post-flox. This comment, from Ruth, is really interesting and insightful. Though she can drink alcohol without issue, she typically abstains:

I am able to drink again but my tolerance is greatly reduced. It won’t actually harm your gaba receptors because alcohol acts on gaba-b instead of gaba-a. I think it promotes healing.

When the alcohol downgrades the gaba-b subunit, I think the body makes repairs to some of the a subunits in order to put things back in balance.

I think when the FQ took out some of your gaba-a receptors your body gave you extra gaba-b receptors. This can make you a lot more receptive to the effects of alcohol. The b unit seems to be able to replace itself faster. That’s why alcohol withdrawal lasts a lot less long than benzodiazepine withdrawal. This is all just my theory. I have nothing to back it up with except my own experience.

Last year I got drunk at the Racine Zoo by accident. They hosted a teacher’s night and served spiked punches with no indication that they were alcoholic. I had what they had labeled as “Lesson Learned Lemonade.” I was thirsty so I slammed a big cup. At first I felt super relaxed and I thought that my nervous system must really be healing. Maybe it was that walk on the beach… and then I felt it. I knew it had been alcoholic. I ended up drunk off my ass, but not so bad that I couldn’t say “gamma amino butyric acid,” ha, ha. I got a brief relapse from that experience, of symptoms I had not had in a long time. After that ended my base line seemed higher.

So I think alcohol is not completely bad. However, it can devastate your gut microbiome, so I am very careful about it. I had a tiny tiny bit of Bailey’s at Christmas. I enjoyed it. Other than the holidays I abstain from alcohol for the sake of my healthy flora.

Although it won’t stop your nervous system from healing, remember that psych symptoms can also stem from an imbalance of healthy vs. unhealthy microbes. Alcohol can worsen that situation considerably so for the foreseeable future it is better to abstain. Farther down the road you will probably be able to have a beer now and then with no ill effects.

Some people have even found that alcohol has helped them. It is a pain reliever and relaxant. It reduces anxiety and stress – even the anxiety and stress that comes with getting poisoned by a pharmaceutical. Stress and anxiety reduction are crucial for healing from fluoroquinolone toxicity. Both Bronwen and Barbara noted that they felt better with moderate alcohol consumption.

Bronwen’s Comment:

As far as booze goes, I actually found one drink helped lessen my symptoms a bit when they were getting overwhelming in the evening – much to my surprise, but I have only ever read one other person that found the same thing – most find the opposite. Again, test yourself! I certainly could not have more than one drink. The liver is struggling along with the other organs, as the clearing house for toxins, so alcohol puts another burden on it.

Barbara’s Comment:

My saving grace is I am allowed wine 😁😁 hallelujah .I have been able to drink alcohol from the begining and in certain times when the pain was bad I swear it helped.

As you can see, reactions to alcohol post-flox vary considerably. So, what should your take-away from this post be? Should you drink alcohol, or not? I can’t answer that for you, because I have no idea how you respond to alcohol, or how much you enjoy consuming it. If alcohol isn’t your drug of choice, and you don’t particularly like it, don’t start drinking because some people have responded positively to its benefits. If you want to drink alcohol, it is, of course, best to do it in moderation. If you want to avoid all things that may trigger a relapse, or that are generally bad for the body, by all means, don’t drink. As with all advice for my floxie friends – it depends, everyone is different, and be careful.

 

Floxie Hope Podcast Episode 24 – PJ

PJ shared his journey through fluoroquinolone toxicity on Episode 24 of The Floxie Hope Podcast. Check it out!

http://www.floxiehopepodcast.com/episode-024-pj/

or

https://itunes.apple.com/us/podcast/floxie-hope-podcast/id945226010

PJ was given IV levofloxacin/levaquin and flagyl in the hospital, and afterward he suffered from multiple severe side-effects including debilitating fatigue, peripheral neuropathy, body-wide numbness, pain, inflammation in all his joints, and more.

He has come a long way, and he is 80% recovered.

PJ is wonderfully insightful and inspirational. Please listen to, review, and share, this episode of The Floxie Hope Podcast. Thanks!!

 

 

 

 

Fluoroquinolones and Statins: A Recipe for Rhabdomyolysis

In May, 2017, WSB-TV 2 Atlanta aired the story, “Clark Howard says near-fatal disease possibly caused by popular antibiotic,” in which the story of how Clark Howard, a popular consumer expert and host of the nationally syndicated Clark Howard Show, was hurt by a combination of ciprofloxacin (a fluoroquinolone antibiotic) and generic Lipitor (a statin). Mr. Howard had a severe and life-threatening reaction to these drugs, and he is quoted in the story as saying, “I felt like death,” and “It was a struggle to walk five steps.” Mr. Howard was admitted to the hospital where he was diagnosed with rhabdomyolysis–a condition where muscles break down rapidly, causing severe strain on the kidneys and, potentially, death.

Both fluoroquinolones alone, and fluoroquinolones combined with statins, have been documented to cause rhabdomyolysis.

Here are some articles about fluoroquinolone-induced rhabdomyolysis:

Here is a news story about Chris Dannelly, who was killed after levofloxacin-induced rhabdomyolysis:

Additionally, here are some articles about fluoroquinolone plus statin induced rhabdomyolysis:

Both fluoroquinolones and statins are known to damage mitochondria, and they are both fluorinated drugs. They are also both widely prescribed–to millions of people annually–often concurrently.

In the article “Musculoskeletal Complications of Fluoroquinolones: Guidelines and Precautions for Usage in the Athletic Population” a description of the basic science behind fluoroquinolone-induced muscle damage (and rhabdomyolysis) is described. The following is a quote from “Musculoskeletal Complications of Fluoroquinolones: Guidelines and Precautions for Usage in the Athletic Population“:

Muscle: Basic Science

Although the etiology of fluoroquinolone-associated muscle disorders has yet to be fully elucidated, evidence supports a relationship with both latent myopathic disorders and the fluorine atom in fluoroquinolones. Despite no history of myopathy, an electromyogram (EMG) performed on a 54- year old woman with apparent ofloxacin-induced rhabdomyolysis demonstrated evidence of myopathy [85]. The patient’s myalgias and muscle weakness resolved upon discontinuation of ofloxacin. It is unknown whether the myopathic findings on EMG were related to the acute rhabdomyolysis or an underlying myopathy. In another case, a 33-year-old man thought to have norfloxacin-induced rhabdomyolysis was found to be susceptible to malignant hyperthermia by in vitro contracture tests [86], which raises the question of a possible link between the 2 conditions. His clinical complaints of myalgia and weakness and laboratory abnormalities resolved 6 months after discontinuing the norfloxacin. The researchers hypothesized that a similar muscle deficit may have accounted for the patient’s susceptibility to malignant hyperthermia and rhabdomyolysis induced by fluoroquinolones. Both malignant hyperthermia and fluoroquinolone-associated muscle disorders are thought to be triggered by a fluorine-containing compound [86]. To further investigate this possible connection, the same French investigators studied muscle function in 3 patients who presented with myalgia, tendinopathy, and arthralgia associated with fluoroquinolone exposure [87]. These results were compared with 3 patients exposed to fluoroquinolones who had no adverse events and 9 subjects with no known muscle disease who had not taken fluoroquinolones. Muscle contraction and metabolism were investigated through the use of histology, in vitro contracture tests, and 31P magnetic resonance spectroscopy (31P MRS). The 3 patients with fluoroquinolone-associated myalgia and weakness displayed similar metabolic abnormalities, whereas the 3 subjects exposed to fluoroquinolones with no adverse effects displayed normal metabolic profiles. These findings led the researchers to conclude that the adverse effects recorded in the 3 patients were related to a pre-existing muscular anomaly revealed by fluoroquinolone treatment. Further support for the hypothesis that fluorine may be the trigger for fluoroquinolone associated myopathy comes from the fact that no adverse muscular events have been reported with unfluorinated quinolones. In addition, steroid myopathy is thought to occur more frequently with fluorinated steroids (ie, dexamethasone and triamcinolone) than with nonfluorinated steroids (ie, prednisone or hydrocortisone) [88-90]. The researchers recommended that any patient experiencing myalgias associated with fluoroquinolone exposure should undergo noninvasive muscle metabolic testing with 31P MRS along with a subsequent muscle biopsy for histoenzymology and contracture tests if a metabolic disorder is found.

Muscle: Clinical Manifestations

A variety of muscle syndromes have been reported in association with fluoroquinolone use, ranging from mild myalgias to life-threatening rhabdomyolysis[78,85-87,91-95]. In fact, some investigators have proposed that myalgias may be the most common adverse effect of fluoroquinolone use [78]. Symptoms, which typically consist of diffuse muscle pain with or without weakness [86,87,91] and perhaps a predilection for proximal muscle groups [85,92], appear to manifest within 1 week after initiation of fluoroquinolone treatment [94] and often resolve within 1-4 weeks after discontinuation of the medication [78,86,91,92], although symptoms that persisted up to 6 months have been reported [86]. Statins may potentiate fluoroquinolone-associated myopathy (emphasis added) [91,92]. Furthermore, an association may exist between an underlying myopathic process and the development of myalgias and/or rhabdomyolysis after fluoroquinolone exposure, as previously discussed.

It is interesting that the authors of “Musculoskeletal Complications of Fluoroquinolones: Guidelines and Precautions for Usage in the Athletic Population” attribute myalgia and rhabdomyolysis to the fluorine atom that is added to quinolones to form fluoroquinolones. The toxicity of fluorine is often overlooked by researchers and “floxies” alike, in part because of the politics associated with assertions that fluorine and fluoride are toxic (they are). As the first sentence in the quote (“Although the etiology of fluoroquinolone-associated muscle disorders has yet to be fully elucidated”) notes though, the exact mechanism through which fluoroquinolones, statins, and fluoroquinolones and statins together, cause adverse reactions is not fully known.

What is known is that fluoroquinolones, and fluoroquinolones combined with statins, can cause rhabdomyolysis, and that rhabdomyolysis can be deadly.

If you are a “floxie” that is on statins, I highly recommend that you talk to your doctor about the case reports linked above and the possibility of rhabdomyolysis and other myalgias being induced by fluoroquinolones, statins, or both.

If you have existing myalgias, including fibromyalgia, I suggest that you take the quote above to your doctor and get off of all fluorinated drugs–as they have been shown to exacerbate myalgias.

I hope that the millions of people on statins, and their doctors, recognize that fluoroquinolones should not be given to people on statins because the two drugs combined can increase the likelihood of rhabdomyolysis and other myalgias.

I’m sorry that Mr. Howard was hurt by ciprofloxacin and generic Lipitor, but hopefully the publicity that his story is getting will serve as a warning for others.

 

Publicizing Fluoroquinolone Warnings

I have such mixed feelings about the FDA’s response to the November, 2015 Antimicrobial Drugs Advisory Committee meeting regarding fluoroquinolone safety. On one hand, I feel like they really did hear those who testified, and they not only listened, they responded in a way that showed that they listened. The FDA did what the Antimicrobial Drugs Advisory Committee recommended they do: they updated fluoroquinolone warnings to note that, “the serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections who have other treatment options.” They not only updated the warning labels, they updated the black-box warnings–the most severe warning a drug can have. I am truly grateful for the steps forward in acknowledging fluoroquinolone adverse-reactions, and I’m hopeful that the updated warning labels will lead physicians and patients to realize that fluoroquinolones are dangerous drugs with potentially devastating consequences.

I wonder though, what good is an updated warning label? In the post, Who Reads the Drug Warning Labels? I go over the problem of people not knowing what is on the warning labels. Are physicians going to read the updated warning labels? Are patients? Is anyone other than the “floxie” community going to realize that the warning labels have been changed?

I appreciate the action taken by the FDA–I really do–but are updated warning labels actually going to change anything? Will fewer people get injured and killed by fluoroquinolones? I certainly hope that a significant portion of doctors hear about the warning label changes, and stop prescribing fluoroquinolones, but, unfortunately, the FDA isn’t taking any major steps to make this happen.

The FDA has no plans to inform individual doctors about the recent warning label changes made to fluoroquinolone warning labels. Even though the black-box warnings, again–the most severe warning label a drug can receive, have been updated to note that fluoroquinolones are associated with disabling and potentially irreversible serious adverse reactions, the FDA is not going to tell doctors about the changes. No “dear doctor” letter will be issued by the FDA. They will not do a massive publicity campaign to let physicians or patients know that the warning labels have been updated. They know about the dangers of fluoroquinolones, and, in their own way, they acknowledge them, but they’re not proactively communicating what they know to patients or physicians.

Since the FDA isn’t going to issue a “dear doctor” letter, it will likely be helpful if we (the people in the fluoroquinolone toxicity community, and those who care about drug safety) give the information the FDA has released to our doctors, local hospitals, and media.

I encourage everyone reading this to please, please, please send this information (that is directly from the FDA) to your doctors, the media, your friends, your loved ones, and anyone else who you think may benefit from the information. People need to know how dangerous Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin, and Factive/gemifloxacin are. In order for them to know how dangerous these drugs are, we need to tell them.

Please forward these FDA releases to those who need this information:

  1. 5/12/16 – Fluoroquinolone Antibacterial Drugs: Drug Safety Communication – FDA Advises Restricting Use for Certain Uncomplicated Infections
  2. 7/26/16 – FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects
  3. July, 2016 Drug Safety Labeling Changes

Since most people don’t actually click on links, I’m also going to copy and paste what the FDA notices said (feel free to share this post with anyone who needs the information too).

Fluoroquinolone Antibacterial Drugs: Drug Safety Communication – FDA Advises Restricting Use for Certain Uncomplicated Infections:

AUDIENCE: Internal Medicine, Family Practice, Pharmacy, Patient

ISSUE: FDA is advising that the serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections who have other treatment options. For patients with these conditions, fluoroquinolones should be reserved for those who do not have alternative treatment options.

An FDA safety review has shown that fluoroquinolones when used systemically (i.e. tablets, capsules, and injectable) are associated with disabling and potentially permanent serious side effects that can occur together. These side effects can involve the tendons, muscles, joints, nerves, and central nervous system.

As a result, FDA is requiring the drug labels and Medication Guides for all fluoroquinolone antibacterial drugs to be updated to reflect this new safety information. FDA is continuing to investigate safety issues with fluoroquinolones and will update the public with additional information if it becomes available.

See the FDA Drug Safety Communication for a list of currently available FDA approved fluoroquinolones for systemic use.

BACKGROUND: The safety issues described in the Drug Safety Communication were also discussed at an FDA Advisory Committee meeting in November 2015.

RECOMMENDATION: Patients should contact your health care professional immediately if you experience any serious side effects while taking your fluoroquinolone medicine. Some signs and symptoms of serious side effects include tendon, joint and muscle pain, a “pins and needles” tingling or pricking sensation, confusion, and hallucinations. Patients should talk with your health care professional if you have any questions or concerns.

Health care professionals should stop systemic fluoroquinolone treatment immediately if a patient reports serious side effects, and switch to a non-fluoroquinolone antibacterial drug to complete the patient’s treatment course.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:

  • Complete and submit the report Online: www.fda.gov/MedWatch/report

  • Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects:

SAFETY ANNOUNCEMENT

The U.S. Food and Drug Administration (FDA) approved changes to the labels of fluoroquinolone antibacterial drugs for systemic use (i.e., taken by mouth or by injection). These medicines are associated with disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system that can occur together in the same patient. As a result, we revised the Boxed Warning, FDA’s strongest warning, to address these serious safety issues. We also added a new warning and updated other parts of the drug label, including the patient Medication Guide.

We have determined that fluoroquinolones should be reserved for use in patients who have no other treatment options for acute bacterial sinusitis, (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and uncomplicated urinary tract infections (UTI) because the risk of these serious side effects generally outweighs the benefits in these patients. For some serious bacterial infections the benefits of fluoroquinolones outweigh the risks, and it is appropriate for them to remain available as a therapeutic option.

Patients must contact your health care professional immediately if you experience any serious side effects while taking your fluoroquinolone medicine. Some signs and symptoms of serious side effects include unusual joint or tendon pain, muscle weakness, a “pins and needles” tingling or pricking sensation, numbness in the arms or legs, confusion, and hallucinations. Talk with your health care professional if you have any questions or concerns (see List of Serious Side Effects from Fluoroquinolones).

Health care professionals should not prescribe systemic fluoroquinolones to patients who have other treatment options for acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and uncomplicated urinary tract infections (UTI) because the risks outweigh the benefits in these patients. Stop fluoroquinolone treatment immediately if a patient reports serious side effects, and switch to a non-fluoroquinolone antibacterial drug to complete the patient’s treatment course (see List of Currently Available FDA-approved Fluoroquinolones for Systemic Use).

Fluoroquinolones are antibiotic medicines that work by killing or stopping the growth of bacteria that can cause illness. They are FDA-approved to prevent or treat certain serious bacterial infections.

The labels of fluoroquinolone medicines already have a Boxed Warning for tendinitis, tendon rupture, and worsening of myasthenia gravis. The labels also include warnings about the risks of peripheral neuropathy and central nervous system effects. Other serious risks associated with fluoroquinolones are described in the labels, such as cardiac, dermatologic, and hypersensitivity reactions. After FDA’s 2013 review that led to the additional warning that peripheral neuropathy may be irreversible, FDA evaluated post-marketing reports* of apparently healthy patients who experienced disabling and potentially permanent side effects involving two or more body systems after being treated with a systemic fluoroquinolone (see Data Summary). We evaluated only reports submitted to FDA, so there are likely additional cases of which we are unaware. The side effects occurred within hours to weeks after starting the fluoroquinolone, and at the time we received the reports, the side effects had continued for an average of 14 months to as long as 9 years after stopping the medicines. Several cases reported that some side effects stopped or improved after discontinuation of the medicine; others reported the side effects worsened or continued.

We previously communicated about these safety issues associated with fluoroquinolones in May 2016. Additional communications about related safety issues associated with fluoroquinolones occurred in August 2013 (peripheral neuropathy) and July 2008 (tendinitis and tendon rupture). The safety issues described in this Drug Safety Communication were also discussed at an FDA Advisory Committee meeting in November 2015.

In addition to updating information in the Boxed Warning, we are also including information about these safety issues in the Warnings and Precautions section of the label. The Indications and Usage section contains new limitation-of-use statements to reserve fluoroquinolones for patients who do not have other available treatment options for acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and uncomplicated urinary tract infections (UTI). The patient Medication Guide that is required to be given to the patient with each fluoroquinolone prescription describes the safety issues associated with these medicines. We are continuing to assess safety issues with fluoroquinolones as part of FDA’s usual ongoing review of drugs and will update the public if additional actions are needed.

We urge health care professionals and patients to report side effects involving fluoroquinolone antibacterials and other drugs to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.

ADDITIONAL INFORMATION FOR PATIENTS

  • Fluoroquinolone antibiotic medicines are associated with disabling and potentially permanent serious side effects that can occur together in the same patient and should not be used to treat certain uncomplicated infections. These uncomplicated infections include acute bacterial sinusitis (ABS), acute worsening of bacterial chronic bronchitis (ABECB), and uncomplicated urinary tract infections (UTI).
  • These side effects can involve the tendons, muscles, joints, nerves, and central nervous system, and can occur within hours to weeks after starting a fluoroquinolone medicine.
  • FDA has updated the Boxed Warning in the labels, added new warnings, and has revised the patient Medication Guide of all fluoroquinolone antibiotics.
  • Contact your health care professional immediately if you experience any serious side effects while you are taking your fluoroquinolone medicine.
  • Before starting a new fluoroquinolone medicine, inform your health care professional if you have previously experienced any serious side effects with another antibiotic.
  • Serious side effects involving the tendons, muscles, joints and nerves include:
    • Swelling or inflammation of the tendons
    • Tendon rupture
    • Tingling or pricking sensation (“pins and needles”)
    • Numbness in arms or legs
    • Muscle pain
    • Joint pain
    • Joint swelling
  • Serious central nervous system side effects include:
    • Depression
    • Hallucinations
    • Suicidal thoughts
    • Confusion
    • Anxiety
  • Other side effects include:
    • Abnormally rapid or irregular heart beat
    • Ringing or buzzing in the ears
    • Vision problems
    • Skin rash
    • Sensitivity of skin to sunlight
    • Headache
    • Trouble falling asleep
    • Fatigue
  • Read the patient Medication Guide you receive with your fluoroquinolone antibiotic prescriptions, which explains the benefits and risks of the medicine.
  • Talk to your health care professional if you have questions or concerns about fluoroquinolone antibiotic medicines.
  • We communicated safety information associated with fluoroquinolones in May 2016, August 2013, andJuly 2008.
  • Report side effects from a fluoroquinolone or any drug to your health care professional and the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of this page.

ADDITIONAL INFORMATION FOR HEALTH CARE PROFESSIONALS

  • FDA has approved label changes that reserve the use of fluoroquinolone antibacterial medicines when treating acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and uncomplicated urinary tract infections (UTI) for patients who do not have alternative treatment options.

  • FDA has also updated the Boxed Warning and the Warnings and Precautions sections of the labels and revised the patient Medication Guide of the fluoroquinolone drug class to describe the serious risk of multiple disabling and potentially irreversible adverse reactions that can occur together.

  • These adverse reactions primarily include tendinitis and tendon rupture, muscle pain, muscle weakness, joint pain, joint swelling, peripheral neuropathy, and central nervous system effects.

  • The adverse reactions can occur within hours to weeks after starting treatment with a fluoroquinolone medicine.

  • Discontinue the fluoroquinolone medicine immediately at the first signs or symptoms of any serious adverse reaction.

  • Avoid fluoroquinolones in patients who have previously experienced serious adverse reactions associated with fluoroquinolones.

  • Serious Adverse reactions of the musculoskeletal system and peripheral nervous system include:

    • Tendinitis/Tendon rupture

    • Muscle pain

    • Muscle weakness

    • Joint pain

    • Joint swelling

    • Peripheral Neuropathy

    • Serious Central nervous system effects include:

      • Psychosis
      • Anxiety
      •  Insomnia
      • Depression
      • Hallucinations
      • Suicidal thoughts
      • Confusion
    • Other adverse reactions include:

      • Exacerbation of myasthenia gravis
      • Prolongation of the QT interval
      • Hypersensitivity reactions/anaphylaxis
      • Photosensitivity/phototoxicity
      • Blood glucose disturbances
      • Clostridium difficile-associated diarrhea
    • Encourage patients to read the Medication Guide that they receive with their fluoroquinolone prescriptions.

    • FDA convened a public advisory committee meeting in November 2015 to discuss the risks and benefits of fluoroquinolone antibacterial medicines for the treatment of ABS, ABECB, and uncomplicated UTI. We also communicated safety information associated with fluoroquinolones in May 2016, August 2013, and July 2008.

    • Report adverse reactions involving a fluoroquinolone or any drug to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of this page.

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Levaquin/levofloxacin Warning Label Changes (Please see July, 2016 Drug Safety Labeling Changes for the other fluoroquinolone label changes:

BOX WARNING (revised)

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

  • Fluoroquinolones, including LEVAQUIN®, 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 LEVAQUIN immediately and avoid the use of fluoroquinolones, including LEVAQUIN, in patients who experience any of these serious adverse reactions. Fluoroquinolones, including LEVAQUIN, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid LEVAQUIN in patients with known history of myasthenia gravis.
  • Because fluoroquinolones, including LEVAQUIN, have been associated with serious adverse reactions, reserve LEVAQUIN for use in patients who have no alternative treatment options for the following indications:
    • Acute exacerbation of chronic bronchitis
    • Acute uncomplicated cystitis
    • Acute sinusitis

WARNINGS AND PRECAUTIONS

Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects (addition)
  • Fluoroquinolones, including LEVAQUIN, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting LEVAQUIN. Patients of any age or without pre-existing risk factors have experienced these adverse reactions.
  • Discontinue LEVAQUIN immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including LEVAQUIN, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.
Tendinitis and Tendon Rupture replaces Tendinopathy
  • Fluoroquinolones, including LEVAQUIN, have been associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur, within hours or days of starting LEVAQUIN, or as long as several months after completion of fluoroquinolone therapy… Tendinitis and tendon rupture can occur bilaterally.
  • The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Discontinue LEVAQUIN immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including LEVAQUIN, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture.
Peripheral Neuropathy (new sentences added)
  • Fluoroquinolones, including LEVAQUIN, have been associated with an increased risk of peripheral neuropathy. Cases of sensory…
  • …minimize the development of an irreversible condition…Avoid fluoroquinolones, including LEVAQUIN, in patients who have previously experienced peripheral neuropathy.

ADVERSE REACTIONS

  • The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
    • Disabling and Potentially Irreversible Serious Adverse Reactions (addition)
    • Tendinitis and Tendon Rupture (replaces Tendon Effects)

PATIENT COUNSELING INFORMATION

Serious Adverse Reactions
  • Advise patients to stop taking LEVAQUIN if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug. Inform patients of the following serious adverse reactions that have been associated with LEVAQUIN or other fluoroquinolone use:
  • Disabling and potentially irreversible serious adverse reactions that may occur together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of LEVAQUIN and may occur together in the same patient. Inform patients to stop taking LEVAQUIN immediately if they experience an adverse reaction and to call their healthcare provider. (addition)
  • Tendinitis and tendon rupture replaces Tendon Disorders

MEDICATION GUIDE

What is the most important information I should know about LEVAQUIN?

Tendon rupture or swelling of the tendon (tendinitis).

  • Stop taking LEVAQUIN immediately and get medical help right away…
  • Worsening of myasthenia gravis (a problem that causes muscle weakness). Tell your healthcare provider if you have a history of myasthenia gravis before you start taking LEVAQUIN. (addition)

What is LEVAQUIN?

  • LEVAQUIN should not be used in patients with acute exacerbation of chronic bronchitis, acute uncomplicated cystitis, and sinus infections, if there are other treatment options available.
  • LEVAQUIN should not be used as the first choice of antibacterial medicine to treat lower respiratory tract infections cause by a certain type of bacterial called Streptococcus pneumoniae.

Before you take LEVAQUIN, tell your healthcare provider if you:

  • have a disease that causes muscle weakness (myasthenia gravis); LEVAQUIN should not be used in patients who have a known history of myasthenia gravis.
  • have nerve problems; LEVAQUIN should not be used in patients who have a history of a nerve problem called peripheral neuropathy

How should I take LEVAQUIN?

Do not skip any doses of LEVAQUIN, or stop taking it, even if you begin to feel better, until you finish your prescribed treatment unless:

  • you have nerve problems. See “What is the most important information I should know about LEVAQUIN?”

  • you have central nervous system problems. See “What is the most important information I should know about LEVAQUIN?”

     

All help in spreading the word about these FDA warnings will be greatly appreciated!

 

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Fluoroquinolones Removed From the Market

Several fluoroquinolones have been removed from the market because they caused acute toxicity and death. The fluoroquinolones that have been removed from the market are not terribly different from the ones that remain on the market in terms of damage done or damage mechanisms.

Here are some of the fluoroquinolones that have been removed from the market:

Omniflox/temafloxacin

In 1992 the fluoroquinolone antibiotic Omniflox/temifloxacin was removed from the US market after causing three deaths.

To note the removal from the market, the FDA released the following statement:

            “The Food and Drug Administration today announced that Abbott Laboratories of Abbott Park, Ill., is voluntarily recalling the broad-spectrum anti-infective drug Omniflox (temafloxacin) tablets, and will halt all further distribution of the drug.

This action is being taken because of severe adverse events associated with the use of the drug that have been reported to the company and to FDA in the first three months of marketing.

Temafloxacin was approved in late January 1992 and marketed in mid-February.  Since that time there have been approximately 50 reports of serious adverse reactions, including three deaths.  There were several cases of severe low blood sugar, especially in very elderly patients with decreased kidney function.  Among the severe reactions there were a number of cases of an unusual complex of adverse reactions consisting of hemolitic anemia (destruction of red blood cells) and other blood cell abnormalities.”

The fluoroquinolones that remain on the market also impair kidney function. From the 2013 Science Daily article, Risk of kidney disease doubled with use of fluoroquinolone antibiotics, “The risk of acute kidney disease is doubled for people taking oral fluoroquinolone antibiotics, according to a new study.” The article pointed out that the risk of acute kidney disease was increased for patients taking cipro/ciprofloxacin, levaquin/levofloxacin, avelox/moxifloxacin and floxin/ofloxacin – fluoroquinolones that remain on the market today.

The fluoroquinolones that remain on the market also cause blood-sugar abnormalities, including severe low blood sugar. A large 2013 study out of Taiwan looked at more than 78,000 patient records and found that, “The researchers found that patients with diabetes who had taken fluoroquinolone antibiotics had higher rates of both hyperglycemia and hypoglycemia compared with those who had taken macrolide antibiotics.” (source) Additionally, in the article, Fluoroquinolone antibiotics and type 2 diabetes mellitus, it is noted that, “Exposure to fluoroquinolone antibiotics is postulated as a risk factor for subsequent development of type 2 diabetes. It is hypothesized that fluoroquinolones induce an intracellular magnesium deficit that can lead to insulin resistance.”

Raxar/grepafloxacin

Raxar/grepafloxacin was removed from the worldwide market in 1999. The FDA withdrawal notice stated:

RAXAR is a fluoroquinolone antibiotic indicated for the treatment of infections caused by strains of bacteria susceptible to grepafloxacin in the following diseases: community-acquired pneumonia; acute bacterial exacerbations of chronic bronchitis; uncomplicated gonorrhea (urethral in males and endocervical and rectal in females); non-gonococcal urethritis and cervicitis.

Glaxo Wellcome has recently concluded an extensive review of the safety of RAXAR and determined that due to an effect of RAXAR on cardiac repolarization, manifested as QT interval prolongation on the electrocardiogram (ECG), some patients may be at risk of a very rare but serious ventricular arrhythmia known as torsade de pointes when treated with the product.

The warning label for Levaquin/levofloxacin (and the other fluoroquinolones that remain on the market) notes that:

“Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval.”

Additionally, a study entitled “Azithromycin and Levofloxacin Use and Increased Risk of Cardiac Arrhythmia and Death” compared the risk of cardiac arrhythmia for U.S. Veterans taking amoxicillin, azithromycin and levofloxacin. The study concluded that:

“Compared with amoxicillin, azithromycin resulted in a statistically significant increase in mortality and arrhythmia risks on days 1 to 5, but not 6 to 10. Levofloxacin, which was predominantly dispensed for a minimum of 10 days, resulted in an increased risk throughout the 10-day period.”

Just like Raxar/grepafloxacin, the fluoroquinolones that are still on the market prolong the QT interval and cause torsade de pointes, which can lead to arrhythmia and death.

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Zagam/sparfloxacin

Zagam/Sparfloxacin was also removed from the market because it caused QT interval prolongation.

Zagam/Sparfloxacin also caused incidents of Stevens Johnson Syndrome:

“When a patient using  Zagam develops SJS or TEN after taking the fluoroquinolone antibiotic treatment, the individual’s topmost skin cells die and fall off. This leaves the deeper layers exposed and unprotected, making it likely for a patient to experience infection and scarring. The sensitive mucous membrane also becomes exposed when the upper layer of skin sloughs off, and may be prone to blistering.” (source)

Trovan/trovafloxacin

Trovan/Trovafloxacin was removed from the market because of its high potential for inducing serious, sometimes fatal liver damage (hepatotoxicity). The wiki entry for Trovafloxacin notes that:

In June 1999 the U.S. Food and Drug Administration advised doctors to limit the prescription of Trovan after it had been found “strongly associated” with 14 cases of acute liver failure and six deaths. The FDA had received over 100 reports of liver problems in people taking Trovan, which was at that time being prescribed at a rate of 300,000 patients per month in the United States. Two days later the Committee for Proprietary Medicinal Products recommended to the European Commission that marketing approval of Trovan be suspended for a year.

One of the best articles about the hepatotoxicity of Trovan/Trovofloxacin is Trovafloxacin, a fluoroquinolone antibiotic with hepatotoxic potential, causes mitochondrial peroxynitrite stress in a mouse model of underlying mitochondrial dysfunction. The article, Mechanisms of Pathogenesis in Drug Hepatotoxicity Putting the Stress on Mitochondria, by some of the same authors, is also enlightening. Liver damage, mitochondrial damage, and ROS overload/oxidative stress are all intricately connected. I highly recommend that you read the two articles linked to (but, man, they’re both really difficult articles). I suspect that both articles hold many of the keys to understanding all fluoroquinolone toxicity reactions. In the post, Article Breakdown – “Mechanisms of Pathogenesis in Drug Hepatotoxicity Putting the Stress on Mitochondria,” I go over some of the implications Mechanisms of Pathogenesis in Drug Hepatotoxicity Putting the Stress on Mitochondria has for floxies.

Interestingly, Trovan/Trovafloxacin has another area of shady history. In Kano, Nigeria, it was used in an improperly conducted trial on children with meningitis. Per the wiki entry for Trovafloxacin:

In 1996, during a meningitis epidemic in Kano, Nigeria, the drug was administered to approximately 200 [3] infected children. Eleven children died in the trial: five after taking Trovan and six after taking an older antibiotic used for comparison in the clinical trial. Others suffered blindness, deafness and brain damage, common sequalae of meningitis that have not been seen in patients treated with trovafloxacin for other infection types.[4][5][6] An investigation by the Washington Post concluded that Pfizer had administered the drug as part of an illegal clinical trial without authorization from the Nigerian government or consent from the children’s parents.[7] The case came to light in December 2000 as the result of an investigation by The Washington Post, and sparked significant public outcry. The most serious error was the falsification and backdating of an ethics approval leader by the lead investigator of the trial, Dr. Abdulhamid Isa Dutse. Dr. Dutse is now the chief medical officer of Aminu Kano Teaching Hospital. The result of the trial was that children treated with oral trovafloxacin had a 5% (5/100) mortality rate compared to a 6% (6/100) mortality rate with intramuscular ceftriaxone.

Between 2002 and 2005 the victims of the Trovan tests in Nigeria filed a series of unsuccessful lawsuits in the United States. However, in January 2009, the United States Court of Appeals for the Second Circuit ruled that the Nigerian victims and their families were entitled to bring suit against Pfizer in the United States under the Alien Tort Statute. A US$75 million settlement with the State of Kano was reached July 30, 2009.[8] Additionally two lawsuits also remain pending in New York, United States.[8] According to Wikileaked US embassy cables, Pfizer’s country manager admitted that “Pfizer had hired investigators to uncover corruption links to federal attorney general Michael Aondoakaa to expose him and put pressure on him to drop the federal cases.”[9]

Additional information about the Kano trial can be found in The Guardian article, Pfizer pays out to Nigerian families of meningitis drug trial victims.

Tequin/gatifloxacin

Tequin/Gatifloxacin was pulled from the market because it caused severe blood sugar reactions such as hyperglycemia and hypoglycemia.

The New England Journal of Medicine article, Outpatient Gatifloxacin Therapy and Dysglycemia in Older Adults, noted that:

“Between April 2002 and March 2004, we identified 788 patients treated for hypoglycemia within 30 days after antibiotic therapy. As compared with macrolide antibiotics, gatifloxacin was associated with an increased risk of hypoglycemia (adjusted odds ratio, 4.3; 95 percent confidence interval, 2.9 to 6.3). Levofloxacin was also associated with a slightly increased risk (adjusted odds ratio, 1.5; 95 percent confidence interval, 1.2 to 2.0), but no such risk was seen with moxifloxacin, ciprofloxacin, or cephalosporins. We then identified 470 patients treated for hyperglycemia within 30 days after antibiotic therapy. As compared with macrolides, gatifloxacin was associated with a considerably increased risk of hyperglycemia (adjusted odds ratio, 16.7; 95 percent confidence interval, 10.4 to 26.8), but no risk was noted with the other antibiotics. Risks were similar in the two studies regardless of the presence or absence of diabetes.”

A more recent study, that looked at a larger population than the NEJM study, Risk of Severe Dysglycemia Among Diabetic Patients Receiving Levofloxacin, Ciprofloxacin, or Moxifloxacin in Taiwan, found that all of the fluoroquinolones on the market increased the likelihood of both hyper and hypo glycemia in diabetic patients:

“A total of 78 433 diabetic patients receiving the antibiotics of interest were included in the study. The absolute risk of hyperglycemia per 1000 persons was 6.9 for moxifloxacin and 1.6 for macrolides. In contrast, the risk of hypoglycemia was 10.0 for moxifloxacin and 3.7 for macrolides. The adjusted odds ratios (AORs) and 95% confidence intervals (CIs) of levofloxacin, ciprofloxacin, and moxifloxacin compared with macrolides were 1.75 (1.12–2.73), 1.87 (1.20–2.93), and 2.48 (1.50–4.12), respectively, for hyperglycemia and 1.79 (1.33–2.42), 1.46 (1.07–2.00), and 2.13 (1.44–3.14), respectively, for hypoglycemia. Patients taking moxifloxacin faced a significantly higher risk of hypoglycemia than those receiving ciprofloxacin. A significant increase in the risk of hypoglycemia was also observed among patients receiving moxifloxacin concomitantly with insulin (AOR, 2.28; 95% CI, 1.22–4.24).”

As mentioned in the Temafloxacin section of this post, fluoroquinolone use has been linked to development of diabetes. Given that all fluoroquinolones cause blood-sugar dysregulation, and two fluoroquinolones have been removed from the market because they caused severe blood-sugar fluctuations, perhaps fluoroquinolones are behind the dramatic increase in both type 1 and type 2 diabetes over the last 30 years. It is a hypothesis that should certainly be looked into.

Conclusion

I struggle with whether or not I think all fluoroquinolones should be taken off the market. Even though I know that they are all dangerous, and sometimes even deadly, drugs, I also know that we are running out of antibiotics in our arsenal and that sometimes dangerous drugs are necessary in order to save a person’s life. I tend to think that Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin, Floxin/ofloxacin, and the other fluoroquinolones, should be severely restricted, and that there should be strict procedures followed when they are prescribed so that it is ensured that they will only be used in life-or-death situations where informed consent is given.

When looking at the fluoroquinolones that have been removed from the market, it always strikes me that they were removed from the market quickly after just a few deaths or a few studies that showed that they are dangerous drugs. The fluoroquinolones that remain on the market (Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin, Floxin/ofloxacin) have also killed people. According to an FDA review with the subject, “Pediatric Exclusivity Postmarketing Adverse Event Review,” between 12/20/1996 and 08/27/2008, 924 people were killed by Levaquin/levofloxacin, including three children. The figures for Cipro/ciprofloxacin, Avelox/moxifloxacin, and Floxin/ofloxacin are similar. So, why do Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin, Floxin/ofloxacin have such staying power? Why are they still on the market when Temafloxacin/Omniflox, Raxar/grepafloxacin, Zagam /Sparfloxacin, Trovan/Trovafloxacin, and Tequin/Gatifloxacin have been removed from the market? I don’t know the answers to those questions–I wish I did. It seems to me that the FDA used to be a stronger, more independent, more effective organization than it is today, and that it used to actually pull dangerous drugs from the market.

Rather than removing dangerous fluoroquinolones from the market, or even imposing meaningful restrictions on the fluoroquinolones that remain on the market, the FDA has instead chosen to increase the size of the fluoroquinolone warning labels. As I have noted before, changed warning labels open the door for lawsuits and that’s a good thing, but it is overall a useless move that is devoid of real change. Not enough doctors or patients read warning labels, and they are a lousy way to communicate the real risks of pharmaceuticals.

The fluoroquinolones that remain on the market are not significantly different from the fluoroquinolones that have been removed from the market. Updating warning labels isn’t keeping people from getting hurt by these dangerous drugs. I understand hesitation to remove them from the market completely, but there should be significant restrictions put on their use. Right now they are not being used prudently or appropriately. That must change. Too many people are being hurt by these dangerous drugs.

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Can Fluoroquinolones Activate Mast Cells?

What is the connection between fluoroquinolone toxicity and mast cell activation / histamine intolerance? Can fluoroquinolones trigger mast cell activation and histamine intolerance?

The symptoms of mast cell activation are similar to those of fluoroquinolone toxicity. According to Mastocytosis Society Canada, the symptoms of mast cell activation are:

skin lesions or sores, skin rash, spots, redness, hives, persistent fatigue, itching, flushing & severe sweating, joint, bone pain, headaches, tachycardia (racing heartrate), eyes tearing/dry, eye pain, persistent body/tissue pain, difficulty exercising, vertigo, episodes of low body temperature, unexplained Vitamin B12 deficiency, scents/odors/chemical reactions, difficult menses (females), numbness & tingling in face and extremities, skin feels on fire, unexplained anxiety, sudden drops in blood pressure, fainting, persistent diarrhea, vomiting, unexplained weight loss, cognitive impairment, sinus problems, chest pain, vision problems, hair loss, mouth sores, nausea, swelling & inflammation, odd reactions to insect stings, anesthesia difficulties, anemia, thyroid problems, decreased bone density, unexplained weakness, shortness of breath, sunlight sensitivity, temperature (hot/cold) sensitivity, difficulty with foods, drinks, anaphylactoid reactions, anaphylaxis, gastrointestinal pain, bloating, unexplained medication reactions, enlarged liver/spleen, liver/spleen/bladder/kidney pain, enlarged lymph nodes, frequent urination, recurring infections, neuropathic pain, constipation, iron deficiency, unexplained bruising, bleeding, malabsorption, intermittent tinnitus or hearing problems.

That’s a pretty comprehensive list of fluoroquinolone toxicity symptoms too. (Though, as I discussed with Dr. Wahls in episode 14 of The Floxie Hope Podcast, all of the multi-symptom, chronic diseases of modernity have more in common with each other than they don’t, and should probably all just be categorized as cellular dysfunction disorders and treated similarly.)

Several floxies who have been able to get a diagnosis from a doctor have come back with a diagnosis of mast cell activation, or a disease that is related to mast cells. For example, one floxie friend’s doctors have diagnosed him with eosinophilia, a disorder that is related to mast cells and histamine intolerance. Other floxies have been diagnosed as histamine intolerant, and instructed to go on a low-histamine diet. As noted above, many floxies have symptoms of mastocytosis, and it is possible that fluoroquinolones activate mast cells and trigger mastocytosis.

Mast cell disorders are considered to be rare, but, according to Mastocytosis Society Canada, “escalation in the prevalence of these patients worldwide has resulted in a flurry of medical research ongoing in numerous countries. This indicates that these disorders may not be rare, but rather have been commonly misidentified and unfortunately for patients worldwide, commonly undiagnosed. Since approximately 2005, every year there are new theories, classifications, and adjustments to the mastocytosis definitions due to escalation of patients presenting with these disorders worldwide.”

I found the following information connecting fluoroquinolones and mast cell activation / mastocytosis:

  • From the International Journal of Tissue Reaction’s article, Effect of levofloxacin and ciprofloxacin injection on permeability of the tail vein in mice and skin microvasculature in rats, “These results suggest that LVFX and CPFX increase vascular permeability through the induction of histamine release from mast cells in rodents.” (LVFX is levofloxacin and CPFX is ciprofloxacin.)
  • From the Journal of Pharmacy and Pharmacology’s article, Characterization of Histamine Release Induced by Fluoroquinolone Antibacterial Agents In-vivo and In-vitro, “Intravenous injection of levofloxacin and ciprofloxacin at 1–10 mg kg−1 produced dose-related elevations in plasma histamine level in anaesthetized dogs. In contrast, levofloxacin was devoid of plasma histamine increment in anaesthetized rats at 100 mg kg−1, whereas ciprofloxacin at the same dose caused endogenous histamine release. Levofloxacin and ciprofloxacin induced non-cytotoxic secretion of histamine from all mast cells tested in a concentration-dependent manner, whereas rat skin and peritoneal mast cells were thirty- to one-hundred-times less sensitive to the effect of fluoroquinolones as compared with the canine skin mast cells.” Note that in studies beagle puppies have been made lame by fluoroquinolones.
  • From the Archives of Toxicology’s article, Differential response of mast cells separated from various organs and basophils of dogs to the fluoroquinolone antimicrobial levofloxacin, “Histamine releases induced by the fluoroquinolone antimicrobial levofloxacin (LVFX) were investigated using mast cells separated from various organs and peripheral basophils of dogs, being the most susceptible species to quinolone derivatives, in both in vivo and in vitro systems. An intravenous infusion of LVFX at 30 mg/kg over a 30-min period produced endogenous histamine release from 5 min, and a maximum at 30 min, in which the plasma LVFX concentration was approximately 50 µM. A close correlation (r=0.87, n=20) between histamine and LVFX concentrations in plasma during the infusion was observed. In the in vitro study, LVFX at 30 µM or more caused histamine release from mast cells separated from the liver and skin, but not from the gastric mucosa, lung, and peripheral basophils. More exactly, the liver mast cells were most susceptible to LVFX among the organs tested. On the other hand, compound 48/80, a prototype histamine liberator, elicited the histamine release from the liver or skin mast cells at 10 µg/ml, and the calcium ionophore A23187 at 1 µM exhibited the histamine release from the mast cells derived from all organs examined. Histochemical analysis revealed that the liver and skin mast cells had positive reaction for both alcian blue and safranin staining, but the gastric mucosa and lung mast cells were only positive for alcian blue staining, indicating that LVFX preferably activated the connective tissue-type mast cells rather than the mucosal-type mast cells. The degranulation of the liver and skin mast cells brought about by either LVFX or compound 48/80, unlike the calcium ionophore A23187, was blocked by pretreatment with pertussis toxin, suggesting the involvement of pertussis toxin-sensitive G proteins. The results obtained from the canine experiments strongly suggest that LVFX induces histamine release from the connective tissue-type mast cells distributed mainly in the liver, somewhat in the cutaneous tissue, through the activation of pertussis toxin-sensitive G proteins.”

The articles noted above are all from animal studies, not human studies, but they show that fluoroquinolones can activate mast cells and histamine release in mammals, and it’s reasonable to think that they may do the same things to humans that they do to dogs. Also, the similarity between fluoroquinolone toxicity symptoms and mastocytosis symptoms, though not a smoking gun, indicate that further studies of the affects of fluoroquinolones on mast cells should be done.

A few good resources for people with mastocytosis, and it’s possible that floxies are in that category, are:

  1. Dr. Theoharides web site
  2. Mastocytosis Society Canada web site
  3. The Low Histamine Chef web site
  4. Alison Vickery’s web site

I suspect that mast cells are profoundly affected by fluoroquinolones and that mast cell activation is a big part of fluoroquinolone toxicity. The potential options, and mechanisms for fluoroquinolone toxicity, are mind-boggling. Add mast cell activation to the list.

 

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