And I Thought a Citizen Petition with the FDA Uses the Language of a Citizen!

Phew! It took three days! In case you are wondering what this is about: I petitioned against the quinolone drug class Cipro and its generic ciprofloxanin to be used only in case of life and death scenario and remove it from the easy reach of doctors for prescribe it for things other, less dangerous drugs can treat. The first petition I filed is written a few blogs back with instructions and links. I submitted that and received an email from the FDA that I need to make it into a “formal” petition with language so decorated with legal jargon that my eyes are still crossed.

I decided to copy-paste my petition here. For one thing it is public anyway so if and when the docket is read and posted online, you can read it. Secondly, if you find that you would like to file a petition yourself, I have worked out some of the language for you and the sections to be referred to in the petition against this drug. I will be attacking each of the quinolone drugs as time goes. The Cipro is first because that drug is by far the most prescribed oral antibiotic in the US (almost 70% of all antibiotics prescribed today is Cipro or its generic equivalent ciprofloxanin). Over 80% of all of the Cipro-ciprofloxanin drugs prescribed are ciprofloxanin, the generic, and only about 10% of the prescriptions are for the brand name. This causes some problems if you read the blog I wrote before this blog. I hope that limiting the drug’s use to extreme life-death situations only and make it available only in emergency rooms, operating rooms, or intensive care will reduce the side effects to next to nothing but making it available for those for whom there is no alternative.

Here is my petition. If you are also filing, please feel free to use my findings and words:

[Code of Federal Regulations]

[Title 21, Volume 1]

[Revised as of April 1, 2014]

[CITE: 21CFR10.30]

Angela A Stanton, Ph.D.

Citizen Petition: existing Docket number: 1jy-8f1z-su92               Date: 10/27/2014

The undersigned submits this petition under the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act or any other statutory provision for which authority has been delegated to the Commissioner of Food and Drugs Administration to request the Commissioner of the Food and Drug Administration to amend a regulation that considers Cipro (ciprofloxacin) to be safe for use as antibiotic drug by general practitioners. The Citizen Angela A. Stanton, PhD, hereby petitions to have Cipro (ciprofloxacin) approval to be reconsidered for life and death situations only.

  1. Action Requested

((3) The petition requests from the Commissioner to take action on behalf of those already injured and those yet to be injured in the future if no action is taken, to prevent such injuries possible on a large-scale by making the drug Cipro (ciprofloxacin) only available in very special cases, such as in the case of life or death and only in the care of emergency rooms, surgical procedures, and intensive care units.

  1. Statement of Grounds

The current approval of Cipro (ciprofloxacin) is based on the safety of the drug | NDA 19-537/S-409, NDA 19-857/S-031, NDA 19-847/S-027, NDA 20-780/S-013 to Bayer Pharmaceutical Corporation from the Center for Drug Evaluation and Research at the Department of Health & Human Services. Application No.: 019537s049, 019847s027, 019857s031 & 020780s013; Approval Date: 03/25/2004

At the time of the approval, the indication for prescription Cipro (ciprofloxacin) was for the following illnesses as per original labeling found at (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/019537s049_019847s027_019857s031_020780s013_Lbl.pdf) in lines starting at 307 “INDICATIONS AND USAGE” through line 505 (emphasis added and some conditions of irrelevance left out)

Adult Patients:

Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae. Serratia  marcescens, Proteus   mirabilis, Providenci  rettgeri Morganell  morganii,  Citrobacter diversus,  Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis.

Acute Uncomplicated Cystitis in females caused by Escherichia coli or Staphylococcus saprophyticus. Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilisLower Respiratory Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter  cloacae, Proteus  mirabilis, Pseudomonas  aeruginosa Haemophilus   injluenzae,  Haemophilus parainjluenzae, or Streptococcus pneumoniae. Also, Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.

NOTE:

Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae. Acute Sinusitis caused by Haemophilus injluenzae, Streptococcus pneumoniae, or Moraxella Catarrhalis. Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella  pneumoniae, Enterobacter  cloacae, Proteus  mirabilis, Proteus  vulgaris, Providencia  stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas  aeruginosa, Staphylococcus aureus (methicillin-susceptible), Staphylococcus  epidermidis, or Streptococcus pyogenesBone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa. Complicated Intra-Abdominal Infections  (used in combination  with  metronidazole)  caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis. Infectious Diarrhea caused by Escherichia  coli (enterotoxigenic strains), Campylobacter jejuni, Shigella boydiit, Shigella dysenteriae, Shigella jlexneri or Shigella sonneit when antibacterial therapy is indicated. Typhoid Fever (Enteric Fever) caused by Salmonella typhi.

NOTE: The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not been demonstratedUncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae.”

Today, October 27, 2014, there are many antibiotic treatments available for most of the illnesses listed above that have proven as effective and cause fewer side effects than Cipro (ciprofloxacin).

The safety advisory warning on the label of Cipro (ciprofloxacin) has been amended several times as a number of adverse effects, unknown at the time of approval, have surfaced. Some of these side effects include damage to the central nervous system that is listed on the original approval as: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has been observed in patients who are exposed to direct sunlight while receiving some members of the quinolone class of drugs. Excessive sunlight should be avoided. The adverse reactions warnings also suggested that it is important to avoid excessive sunlight or artificial ultraviolet light while receiving ciprofloxacin and to discontinue therapy if phototoxicity occurs. Furthermore it was advised to discontinue treatment; rest and refrain from exercise; and inform their physician if patients who took ciprofloxacin experience pain, inflammation, or rupture of a tendon.

Under Drug Interactions (lines 506 through 540, also emphasis added and only concerns of importance listed)

“As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life.

Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.

Animal studies have shown that the combination of very high doses of quinolones and certain non-steroidal anti-inflammatory agents (but not acetylsalicylic acid) can provoke convulsions”

Please note that at the time of the drug interactions listed, it was not known that any NSAD taken together with quinolones such as Cipro (ciprofloxacin) at standard low doses also causes major interactions. It was also not clear that the prescription of steroid drugs for use in combination with Cipro (ciprofloxacin) also in low dose caused major adverse reactions. While prescribing quinolones, such as Cipro (ciprofloxacin), as usual, doctors and pharmacies have not apparently heard or read the message and even today continuously prescribe Cipro (ciprofloxacin) and steroid and/or NSAD, causing major and often irreversible complications. Some adverse effects happen immediately upon taking the first Cipro (ciprofloxacin) tablet, others later but prior to finishing full prescription and yet other several months later! This makes the connection to Cipro (ciprofloxacin) very hard to prove pending blood tests that are now being developed and used to evaluate the reasons for the damage.

FDA Adverse Effect Update:

To date there have been two FDA requests for label change on Cipro (ciprofloxacin) and other quinolone class drugs: 2012 and 2013. This is indicative that some of the adverse reactions appear years after the drugs were taken and not always after the first application—as if there was a threshold level for each person beyond which there is no return.

FDA updates on the adverse effects of fluoroquinolones drugs, including Cipro (ciprofloxacin) in 2012 states:

“The results of FDA’s recent review of the Adverse Event Reporting System (AERS) database indicate that although the risk of peripheral neuropathy is described in the drug labels of each marketed systemic fluoroquinolone, the potential rapid onset and risk of permanence were not adequately described. The recent AERS review evaluated cases of fluoroquinolone-associated peripheral neuropathy with an outcome of “disability, reported between January 1, 2003 and August 1, 2012. The review showed a continued association between fluoroquinolones use and disabling peripheral neuropathy… FDA has required manufacturers of systemic fluoroquinolone drugs to make revisions to the drug labels (Warnings/Precautions and Warnings and Precautions sections) and the Medication Guides. These label changes are to better characterize the risk of peripheral neuropathy associated with the class of systemic fluoroquinolones. If a patient develops symptoms of peripheral neuropathy, the fluoroquinolone should be stopped, and the patient should be treated with an alternative non-fluoroquinolone antibacterial drug, unless the benefit of continued treatment with a fluoroquinolone outweighs the risk.” (page 3 on http://www.fda.gov/downloads/Drugs/DrugSafety/UCM365078.pdf)

This particular label update by the FDA did not yet state that peripheral neuropathy can be permanent and other conditions, such as tendon tears (partial or full) can be permanent disabling conditions. Though it mentions the seriousness, it does not equate the serious condition to patient suffering and quality of life altering complications.

FDA updates on the adverse effects of fluoroquinolones drugs, including Cipro (ciprofloxacin) in 2013 states:

 “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” requesting that the label of all approved fluoroquinolones drug labels be modified with the possible permanency of peripheral neutropathy, a condition affecting the central nervous system, often causing permanent disability.” (Emphasis added)

Please note that still in the second label change the FDA does not mention the importance of patient suffering and the disabling condition resulting from tendon injuries. As a tendon injured citizen, I can attest to the drug’s permanent disabling effect in pain as well as ability to walk and accomplish work.

It is important to note that now there have been many scientific studies showing the oxidative effects of quinolones, in particular that of ciprofloxacin (Talla, Veerareddy, J Young Pharm. 2011, Oct-Dec; 3(4: 304-309), DNA mutations as a result of fluoroquinolones (Pallo-Zimmarman et al., Compendium, July 2010: E1-E9), Mammalian Mitchochodrial cell damage (Kalghatgi et al., Sci Transl Med 5, 192ra85 (2013)), the effects of UV A light on fluoroquinolones (Perrone et al., Toxicological Sciences 69, 16-22 (2002): 16-22). Additional studies show that the damage of “sun” is not just that of enhanced sunburn predisposition during the period of taking quinolones, including Cipro (ciprofloxacin), but that the phototoxicity implies an underlying further damage to mitochondrial DNA and whether the UV light is A or B matters (Akter et al., Free Radic Biol Med. 1998 May;24(7-8):1113-9.; Dykens, et al., Expert Review of Molecular Diagnostics [2007, 7(2):161-175] (2007): 161-175).

In light of all these adverse effects whose importance is noted but underestimated even in the second label update request by the FDA, as a citizen I petition to modify the label of the quinolone drugs, starting with Cipro (ciprofloxacin) as a result of oxidative stress and DNA mutation causing permanent damage and lifelong disability in the human body. I petition to modify the label providing instructions to practitioners,   permitting only limited access to the drug based on life threatening circumstances and made only available in emergency rooms, surgical procedures, or life saving measures in intensive care.

It is my belief that at this point the drug’s benefits, for treating simple infections that can be treated by less harmful medicines, have been exceeded by the injuries it causes as adverse effects, which are often irreversible. It is also my experience – consistent with the FDA database – that the quinolone drug class, especially Cipro (ciprofloxacin) is the most often prescribed oral medicine for any and every bacterial infection, no matter what the cause. The over-prescription of this drug has caused a decline in its effectiveness. This further strengthens the argument that the risks of taking this drug now greatly outweigh the benefits it provides.

In order for the benefit of the drug to be outweighed by its adverse effects, the adverse effects need to be temporary and less than debilitating to handicap level and the benefit must be significant. Since many of the adverse effects are now understood to be long-lasting, some irreversible for life, and Cipro (ciprofloxacin) is losing its effectiveness in light of many resistant bacterial classes, Cipro (ciprofloxacin) has exceeded the expected benefits with respect to adverse effects and thus should be removed from everyday use.

1. Environmental Impact

N/A

2. Economic Impact

N/A

3. Certification

The undersigned certifies, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner which are unfavorable to the petition.

______________________________________________________________(Signature)

Angela A. Stanton, Ph.D._____________________________(Name of petitioner)

_____________________(Mailing address)

______________________(Telephone number)

Your comments are welcome as always!

Angela

 

 

About Angela A Stanton, Ph.D.

Angela A Stanton, PhD, is a Neuroeconomist focusing on chronic pain, electrolyte homeostasis, and genetics. She lives in Southern California. Her current research is focused on migraine cause, prevention and treatment without the use of medicines. As a forever migraineur from childhood, her discovery was helped by experimenting on herself. She found the cause of migraine to be at the ionic level, associated with disruption of the electrolyte homeostasis, resulting from genetic variations of all voltage gated channels that modulate electrolytes and voltage in the brain, insulin and glucose transporters, and several other related variants, such as the MTHFR variants of the B vitamin methylation process and many others. Migraineurs are glucose sensitive and should avoid eating carbs as much as possible. As a result of the success of the first edition of her book and new research and findings after treating over 4000 migraineurs world wide, all ages and both genders, she is now finishing the 2nd edition. The 2nd edition is the “holy grail” of migraines, incorporating all there is to know and also hypotheses. It includes an academic research section with suggestions for further research. The book is full of citations to authenticate the statements she makes to be followed up by those interested and to spark further research interest. It is a "Complete Guide". Due out in the summer of 2017. Dr. Stanton received her BSc at UCLA in Mathematics, MBA at UCR, MS in Management Science and Engineering at Stanford University, PhD in NeuroEconomics at Claremont Graduate University, and fMRI certification at Harvard University Medical School at the Martinos Center for Neuroimaging for experimenting with neurotransmitters on human volunteers. For relaxation Dr. Stanton paints and photographs. Follow her on Twitter at: @MigraineBook
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2 Responses to And I Thought a Citizen Petition with the FDA Uses the Language of a Citizen!

  1. rubyr8 says:

    Wow, you are right reading that does leave your eyes reeling for awhile but I digress you do have a very salient point.
    Even in my country it is over-prescribed, my sister is a pharmacist and agrees mostly with your write up.
    Good luck with your petition, hope it gets the attention it deserves.

    Liked by 1 person

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