Jay S. Cohen M.D.       http://medicationsense.com      1337 Camino Del Mar   Suite C       Del Mar, CA 92014       Phone: 858.345.1760       Fax: 858.509.8944


New Warnings for Cipro, Levaquin, and other Quinolone Antibiotics

Serious Reactions Continue to Be Reported.

This article is an updated version of my original article on reactions with fluoroquinolone antibiotics I posted in the July-Sept.2003 newsletter.

Since the Annals of Pharmacotherapy published my article1 on neuropathies with quinolone antibiotics in December 2001, I continue to receive frequent reports from people who have developed severe, sometimes disabling symptoms while taking fluoroquinolone antibiotics (quinolones) such as Cipro, Levaquin, Floxin, or Tequin.  Many of these people are young and physically fit -- some were high intensity athletes -- until taking a quinolone.  These reactions are very serious, and many people have written to me seeking information or suggestions.  This article represents my knowledge of the issue.

New Warnings
Currently available quinolones available in the U.S. include Avelox (moxifloxacin), Cipro (ciprofloxacin), Factive (gemifloxacin), Floxin (ofloxacin), Levaquin (levofloxacin), Noroxin (norfloxacin), and Tequin (gatifloxacin).  Over the years, other quinolones have been withdrawn from the market.  In autumn 2004, the FDA mandated new warnings in the labeling of quinolones about nerve injuries associated with quinolones.  The new warning reads:

"Peripheral Neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including [name of specific quinolone].  [The drug] should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation in order to prevent the development of an irreversible condition."

This is an important, overdue warning.  Moreover, it specifically tells doctors to discontinue treatment if any of these symptoms occur.  You can find this warning regarding Cipro on page 823 of the 2005 Physicians' Desk Reference (PDR).  However, you will not find this warning in the write-ups of Levaquin, Floxin, or Tequin in the 2005 PDR (I did not check the other quinolones).  You can find the warnings elsewhere.  For example, some are listed at the FDA website: www.fda.gov/medwatch/SAFETY/2004/sep04_quickview.htm.  You can also find this warning in the package inserts for each of these drugs.   

In addition, quinolone write-ups in the 2005 PDR contain "Warnings" sections that list "Central Nervous System Disorders."  The Cipro write-up lists dizziness, confusion, tremors, hallucinations, depression, and an increased risk for people predisposed to seizures.  The Levaquin write-up (page 2503) lists tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, may increase risk for people predisposed to seizures, and rarely, suicidal thoughts or acts.  Tequin (page 1079) and Floxin write-ups (page 2497) contain similar lists.  All quinolone write-ups also contain lists of symptoms involving the central and peripheral nervous system under the section for "Adverse Reactions."  Lists of reactions involving other systems such as cardiovascular or musculoskeletal can also be found in this section.

Quinolone write-ups also contain specific warnings about tendon ruptures, stating that some have required surgical repair or resulted in prolonged disability.  Tendon ruptures can occur during or after quinolone therapy.  Treatment with steroids may increase the risk of tendon rupture with quinolones.

Also worth noting, the write-ups for some quinolones state that these drugs have been associated with changes in people's electrocardiograms.  Called "prolongation of the QT interval," this adverse effect may be associated with abnormal cardiac rhythms.  Some of these arrhythmias can be serious, such as the "torsade de pointes" listed with Levaquin.  This reaction alone should make doctors pause before prescribing Levaquin or quinolones that cause QT interval prolongation.  Other drugs (e.g., Seldane, Hismanal, Propulsid) were withdrawn because they cause QT interval prolongation.

The Potential Impact of the New Warnings
Overall, it should be helpful that quinolone package inserts now include warnings about peripheral neuropathies (injuries to the nerves outside the brain or spinal cord).  The question is, will doctors notice these warnings?  Doctors do not reread package inserts or the PDR every time they prescribe the same drug.  Moreover, the package inserts of quinolones are very long, and the information can easily be overlooked.

Perhaps the greatest usefulness of the new warnings may be for patients who develop side effects with quinolones and who consult the PDR, or for doctors who consult the PDR after patients complain about side effects.  Either way, the hope is that these warnings will lead to quicker recognition of these side effects and prompt discontinuation of the quinolone.  The quicker the drugs are stopped, the better.  My belief is that once you develop a problem, even if it is minor, with a quinolone, you should not take any quinolone again.  It is believed that toxicities with quinolones are cumulative, so reexposure is risky.

Hopefully, the new warnings will also make doctors pause before prescribing quinolones for common infections of the bladder, prostate, or sinuses.  The seriousness of potential reactions -- tendon ruptures, nerves injuries, joint pains, cardiac effects -- warrant a very cautious attitude about prescribing quinolones.  There is some evidence that by their chemical major, quinolones may be toxic to human tissue.  At the same time, quinolones can be very important antibiotics when used properly, and most people given quinolones do not develop serious side effects.  Nevertheless, quinolones are overused for minor conditions when other, safer antibiotics would suffice.  My stance is that quinolones should be reserved for serious infections for which other antibiotics have been ineffective or for organisms that are only sensitive to quinolones.  Even then, quinolones should be used carefully with close monitoring for side effects.

At the very least, people being placed on quinolones should be warned about possible side effects: joint, muscle, or tendon pain or rupture, nerve pain (burning, electrical sensations, tingling), muscle weakness, thinking or memory problems, heart palpitations, rapid heart rate, gastric problems, skin rash, or psychological symptoms.  People have a right to informed consent, which means that they should be advised of the possible benefits and risks of any treatment.  Because quinolone reactions sometimes occur quickly, patients need to be informed so that they can alert their doctors.  Unless there is a medically urgent reason to the contrary, quinolone treatment should be stopped immediately.

Treatment Possibilities
This is the information I have posted previously with some new wrinkles.  However, please realize that these are simply suggestions.  There are no known specific antidotes to quickly reverse a quinolone reaction.  By necessity, people have tried many different treatment methods, and results are spotty.  I do not know if any of the suggestions below are highly effective, but having experienced a severe, years-long disability myself in the mid-1990s (not a quinolone reaction) and now having improved considerably, I encourage people to keep asking questions and trying things.

Many people sustaining quinolone reactions turn to their regular doctors and specialists.  Some doctors try to be helpful, but many are uninformed about quinolone reactions or uninterested.  Some doctors just cannot conceive that quinolones could cause such serious, long-term reactions.  Doctors are taught that drug companies and the FDA conduct intensive research to ensure the safety of new drugs.  This is untrue.  According to an article in JAMA: "Discovery of new dangers of drugs after marketing is common.  Overall, 51% of approved drugs have serious adverse effects not detected prior to approval2."  Many doctors are not aware of this.

In any event, doctors may suggest a variety of medications.  For nerve or neuropathic pain (tingling, burning or electrical sensations), drugs such as Neurontin (gabapentin) or anti-seizure drugs may be recommended.  Tricyclic antidepressants are known to help some neuropathies.  The best-known tricyclic is amitriptyline (Elavil), which is sedating, so it might also be helpful for people also experiencing insomnia.  For others, it will be too sedating.  Nortriptyline is as effective as amitriptyline for neuropathies, and nortriptyline generally causes less sedation or other side effects.  Desipramine is similar to nortriptyline and may actually increase energy in people who are fatigued.  In others, desipramine can cause anxiety.  Avoid tricyclics in people with cardiac conditions or symptoms.

Muscle spasms, twitching, tremors, and seizures may be helped with long-acting anti-anxiety benzodiazepines such as clonazepam (Klonopin) or diazepam (Valium).  Some doctors may recommend Xanax, which is a poor muscle relaxant but effective for reducing anxiety.  Xanax is fine for PRN (intermittent) use.  Xanax works fast and is not usually sedating, but when taken three or four times every day, it can quickly cause dependency with severe withdrawal reactions.  The long-acting benzodiazepines can also cause dependency, but in my experience, less frequently than Xanax does.  With any of these drugs, the lowest dosage that works should be used.

SSRI antidepressants (Zoloft, Paxil, Prozac, Effexor, etc.) may be helpful for depression.  Because some people's nervous systems are very sensitive to these drugs, they should be started at very low doses and increased very gradually, if necessary.  By "lower doses," I mean doses that are lower than the lowest doses recommended by manufacturers.  For example, although the usual starting dosage of Prozac is 20 mg/day, 5 mg/day has been effective in clinical studies and works for many people.

Anti-inflammatory drugs are controversial: some people have written to me that they have been helped with anti-inflammatory drugs, especially for muscle/joint/tendon pain, but others have written that these drugs have worsened their conditions.  Corticosteroids (cortisone, etc.) are very controversial.  Doctors sometimes prescribe steroids in the hope of reducing the reactions, but many people have written that steroids actually made their reactions worse.  Steroids can increase the risk of tendon ruptures with quinolones.

There may be other medications used for quinolone reactions that I have not listed here.  This list is not intended to be comprehensive.  It merely reflects my knowledge, which is limited.  For more complete, updated information, please ask your doctor or pharmacist.  Also, check the websites listed at the bottom of this article.

Alternative Possibilities
Magnesium in doses of 400-1000 mg/day may be useful for reducing neuropathic pain or muscle spasms in some people.  Feedback from quinolone sufferers about magnesium has been mixed.  The U.S. recommended daily amount of magnesium is 320 mg for women and 400 mg for men.  Use of higher dosages should always be done with the supervision of a healthcare practitioner.  Seniors, people with kidney disorders, and those taking medications for cardiovascular or neurological disorders should have medical supervision even for RDA doses of magnesium.  Interestingly, Dr. David Flockhart also recommends magnesium for quinolone reactions.  Dr. Flockhart recommends low doses of milk of magnesia (1 or 2 teaspoons twice-daily), to be taken for several months.  His theory is that because of the affinity of minerals for quinolone antibiotics, magnesium might help leech some remaining fluoroquinolone molecules from the tissues. 

I am not a fan of milk of magnesia, which is a laxative.  If the goal is to absorb magnesium in order to get it into the tissues, chelated magnesium (e.g., magnesium aspartate, magnesium glycinate) or a magnesium solution (e.g., magnesium chloride) are absorbed better than milk of magnesium or cheap magnesium supplements.  It has also been suggested that magnesium could be used with calcium and other minerals.  The fact is, no one knows.  There's little solid science, so it is trial and error.  (For more information on magnesium, please go to the other magnesium sections of this website.)

B-vitamins have been reported to reduce tingling.  Pyrodoxine (vitamin B6) and pantethine (a derivative of pantothenic acid) have been reported to improve some types of nerve pain.  One person wrote to me that high doses of lecithin had helped with memory problems.  This is not farfetched.  Lecithin contains several substances essential for normal nerve functioning.  One of these is phosphatidylcholine.

For anxiety or agitation, or to increase GABA in the nervous system, many alternative doctors recommend taking GABA, which is an amino acid.  GABA has some similar qualities to Valium and Xanax, and it may be helpful for anxiety, nervousness, or insomnia.  Too much GABA can cause sedation.  Inositol is also used for treating anxiety.

There are several alternative methods for reducing inflammation.  Omega-3 fatty acids (fish or flax oils) increase the anti-inflammatory prostaglandins (PGE3) in cell membranes.  GLA, found in primrose or borage seed oil, increases PGE1, which is also anti-inflammatory.  Studies have shown that high doses of omega-3 fatty acids and of GLA reduce the pain of arthritis.  This method takes time, several months, because it requires a rebalancing of the prostaglandins in the membranes of trillions of cells, but the ultimate reduction in inflammation is better, in my experience, than with prescription anti-inflammatory drugs.  Omega-3 fatty acids and GLA are just two of many alternative methods for reducing inflammation.

If you are interested in alternative supplement and diet possibilities, I would suggest consulting with a knowledgeable alternative practitioner.  Many doctors have adopted alternative methods because they became dissatisfied with the drug-oriented mindset of mainstream medicine.  In my experience, alternative doctors are much more receptive to patients' concerns about medication side effects.  Good alternative practitioners are also far more knowledgeable about the biochemical systems of the body.  They have tests to measure people's levels of fatty acids, amino acid, antioxidants, minerals (including toxic minerals), and many other factors that may explain why some people are more vulnerable to certain diseases or reactions.  Good alternative doctors are knowledgeable about magnesium and other minerals, GABA, omega-3 fatty acids, and many other human-compatible therapies.  For example, alternative practitioners use alpha lipoic acid for treating neuropathies.  Alpha lipoic acid has long been used in Europe, and there is a considerable medical literature on this substance.  Few mainstream doctors are aware of alpha lipoic acid, magnesium, or the other natural remedies I have discussed above.  I cannot say that alternative doctors have the answer to quinolone reactions.  I can only say that it is another option worth considering.

If you run out of options with your mainstream doctors and would like to consult with an alternative practitioner, ask your friends whom they have seen and recommend.  Half of the population has consulted with an alternative practitioner at one time or another.  You can also find practitioners via the websites of the American College for the Advancement of Medicine (www.ACAM.org) or the American Holistic Medical Association (www.AHMA.org).  One caveat: many alternative practitioners do not accept insurance and many of their tests are not covered by health insurance plans.  Another caveat: different alternative practitioners use different methods; ask questions, ask for written information; many offices will send brochures or other information about practitioners' methods.

In Summary
Fluoroquinolone-linked reactions are nasty.  These reactions vary from minor to extremely serious.  Some are disabling.  Recovery varies from individual to individual, with some reactions resolving quickly and others lasting years.  As far as I know, none of the companies that manufacture quinolones has attempted to study how to help people sustaining severe quinolone reactions.  The manufacturers seem content to list tendon ruptures or neuropathies when the FDA finally demands it, while ignoring the thousands of people who are suffering.  To me, this is unconscionable.  Then again, if you have looked at my website, you know that for many years I have been concerned about the failure of the drug industry to adequately ensure drug safety.

If you have not already done so, please submit a Medwatch report to the FDA about your quinolone reactions.  The FDA moves slowly, but with enough reports and pressure from patients (and some doctors, hopefully), the FDA will examine a problem.  Filing a Medwatch report is easy to do at: www.fda.gov/medwatch/report/consumer/consumer.htm.  Or call 800-FDA-1088).

 I regret that I cannot provide you with more specific, proven treatment options for these terrible reactions.  I hope that some of the suggestions above are helpful or at least provide ideas that stimulate other possibilities.  Whether you have a mild, moderate, or severe reaction to a quinolone, I hope that your condition resolves soon.

Sincerely,

Jay S. Cohen, M.D.

References
1.  Cohen, JS.  Peripheral Neuropathy with Fluoroquinolone Antibiotics.  Annals of Pharmacotherapy, Dec. 2001;35(12):1540-47.
2.  Moore, TJ, Psaty, BM, Furberg, CD.  Time to act on drug safety.  JAMA 1998;279(19):1571-3.

Websites with information regarding fluoroquinolone reactions: Patient reports, articles, and information.
http://www.geocities.com/quinolones/
http://www.geocities.com/quinolones/adrs.html
http://www.drugvictims.org/
http://www.fqvictims.org/
http://www.fqresearch.org/
http://health.groups.yahoo.com/group/quinolones/messages/?threaded=1
http://www.rxlist.com/rxboard/levaquin.pl
http://www.askapatient.com/viewrating.asp?drug=20635&name=LEVAQUIN
http://www.askapatient.com/viewrating.asp?drug=19537&name=CIPRO
http://www.worstpills.org/recent_postings.cfm   
http://groups.yahoo.com/group/fq_research
http://www.MedicationSense.com.   Dr. Cohen's 2 previous articles on quinolones are listed on the home page in the following newsletters: Jan.-Mar. 2004 and July-Sept. 2003.





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