Quinolone Vigilance Foundation Comments submitted for FDA Pediatric Advisory Committee Meeting

 

Quinolone Vigilance Foundation Comments submitted for FDA Pediatric Advisory Committee Meeting

This is what QVF submitted to Dr. Walter Ellenberg at the FDA and will be presented at the FDA Pediatric Advisory Committee meeting on September 23 in Bethesda, Maryland.

 

 

August 25, 2014



Walter Ellenberg, Ph.D.
Office of the Commissioner, Office of Pediatric Therapeutics
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 32, Room 5154
Silver Spring, Maryland 20993

Dear Dr. Ellenberg and Members of the FDA Pediatric Advisory Committee:

Thank you for your work on important Pediatric Drug Safety issues. Below are comments from the Quinolone Vigilance Foundation for the September 23, 2014, FDA Pediatric Advisory Committee Meeting regarding the fluoroquinolone antibiotic, Levaquin.

Thank you for your attention to our comments. I look forward to your feedback.

Respectfully,

Rachel Brummert
President/Executive Director
Quinolone Vigilance Foundation
www.SaferPills.org
Rachel@SaferPills.org




COMMENT #1: April 17, 2014, the FDA wrote a report titled, “Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Pharmacovigilance Review,” subject “Disabling Peripheral Neuropathy Associated with Systemic Fluoroquinolone Exposure.” This report was signed by Min Chu Chen, Acting Division Director; Allen Brinker, Team Leader; Jane Gilbert, Reviewer; Kelly Cao, Team Leader; and Debra Boxwel, Reviewer and describes two important issues:

1. Potentially permanent peripheral neuropathy.
   

1. Possible mitochondrial toxicity which has been implicated in serious, life-ending, adverse events, including-but-not-limited-to neurodegenerative diseases such as Parkinson’s, Alzheimers, and ALS.
   

This report also describes two flurouqinolones (Trovafloxacin and Gatifloxacin) which have already been removed from the market due to mitochondrial toxicity.

Based on this April 17, 2013 FDA report, based on the FDA’s own research, and using the FDA’s own words, a Citizen Petition was submitted to Dr. Hamburg, FDA Commissioner, in June 2014 by Dr. Charles Bennett, University of South Carolina, asking for the following Black Box Warning to be added immediately to the Levaquin label.

WARNING: POSSIBLE MITOCHONDRIAL TOXICITY
Fluoroquinolones may cause Mitochondrial Toxicity which may result in conditions such as peripheral neuropathy, hepatoxicity, glucose disturbances, phototoxicity, developmental disorders of the brain, optic neuropathy, neuropathic pain, hearing loss, muscle weakness, cardiomyopathy, lactic acidosis, Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS).

COMMENT #1 REQUEST FOR THE PEDIATRIC ADVISORY COMMITTEE: Please reconsider the use of Levaquin for the pediatric population based on the April 17, 2013 FDA safety report and research, as well as, the Citizen Petition submitted to Dr. Hamburg asking for an immediate Black Box Warning for possible Mitochondrial Toxicity. As described by the FDA, peripheral neuropathy may be permanent and neurodegenerative diseases, such as Parkinson’s, Alzheimers, and ALS are life-ending.


COMMENT #2: FDA Adverse Events Reporting System (FAERS) data indicate extensive psychiatric adverse events associated with Levaquin as indicated below. Some of these adverse events are on the Levaquin label; some are not.

Levaquin FAERS Psychiatric Adverse Events Compared with the Current Levaquin Label
Adverse Event	% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012
Insomnia	4.1%
Anxiety	3.0%
Depression	2.7%
Confusional state	2.2%
Feeling abnormal	1.7%
Loss of consciousness	1.4%
Hallucination	1.3%
Disorientation	.8%
Nightmare	.8%
Agitation	.7%
Delirium	.7%
Depressed level of consciousness	.7%
Psychotic disorder	.7%
Amnesia	.6%
Coma	.6%
Disturbance in attention	.6%
Panic attack	.6%
Memory impairment	.5%
Nervousness	.5%
Suicidal ideation	.5%
Restlessness	.5%

Based on the extensive list of Levaquin associated psychiatric adverse events, Dr. Charles Bennett, University of South Carolina, will submit a Citizen Petition to Dr. Hamburg in September, 2014, asking for the following Black Box Warning to be added to the Levaquin label.

WARNING: SERIOUS PSYCHIATRIC EVENTS

Serious psychiatric events including, toxic psychoses, hallucinations, paranoia, suicidal thoughts or acts, loss of consciousness, delirium, depressed level of consciousness, amnesia, coma, and memory impairment have been reported in patients receiving fluoroquinolones, including Levaquin. These events may start during treatment or may be delayed and start days, weeks, or months after the last dose.

Consistent with the FAERS data, a social network of individuals who report experiencing Levaquin Adverse Events report the following Psychiatric Adverse Events as indicated in the table below.

Survey Question: Describe “any psychiatric symptoms Due to Fluoroquinolone Toxicity (depression, anxiety, psychosis, etc)?”
Anxiety
Depression
Insomnia
Panic attacks
Brain fog and/or cognitive impairment
Depersonalization and/or derealization
Thoughts of suicide
Psychosis and/or hallucinations
Nightmares and/or abnormal dreams
Impaired memory
Emotional outbursts (crying/giggling) and/or mood swings
Paranoid and/or fearful
Agitation
Attention deficit and/or lack of concentration
Sensation of impending doom
Difficulty reading and/or doing math
Confusion
Mania and/or hyperactivity
Rage and/or temper flares

COMMENT #2 REQUEST FOR THE PEDIATRIC ADVISORY COMMITTEE: Please reconsider the use of Levaquin for the pediatric population based on FAERS psychiatric adverse events data, social network survey data, as well as, the Citizen Petition to be submitted to Dr. Hamburg asking for an immediate Black Box Warning regarding Serious Psychiatric Events.


COMMENT #3: As indicated above, FAERS data and the social network survey data indicate a potential concern for suicidal thoughts or ideation. Although data specific to the pediatric population is not available, this is a significant concern in general.

COMMENT #3 REQUEST FOR THE PEDIATRIC ADVISORY COMMITTEE: Please reconsider the use of Levaquin for the pediatric population based on FAERS suicidal ideation adverse events data, social network survey suicidal thoughts data, as well as, the Citizen Petition to be submitted to Dr. Hamburg asking for an immediate Black Box Warning regarding Serious Psychiatric Events which includes language regarding suicidal thoughts or acts.


COMMENT #4: ABC News ran a story February 24, 2014, “Doctors Probe Polio-Like Illness in California Kids.” This story describes the following:
“Sofia's problems began when her parents noticed she was having trouble breathing. After treatment by her pediatrician didn't help, Sofia spent four days in the hospital, but her breathing was still not completely clear. Her doctor suspected it might be pneumonia and gave her an antibiotic, but as the family was leaving the doctor's office the little girl reached her left hand out for a toy, and, her mother said, ‘mid-grasp her left hand dropped.’"

As noted in this story, it appears Sophia was given an antibiotic for possible pneumonia proximate to the onset of paralysis. Because some of the Levaquin pediatric clinical trials were for pneumonia, it is possible that Sophia was given Levaquin.

FDA Levaquin FAERS data include reports of adverse events including 44 cases of “paralysis” between November 1997 and January 2010. If only 1% to 10% of actual adverse events are reported to FAERS, the actual number of paralysis adverse events could be 440 to 4, 400.

COMMENT #4 REQUEST FOR THE PEDIATRIC ADVISORY COMMITTEE: Please contact Dr. Keith Van Haren, Lucile Packard Children’s Hospital, Stanford and Dr. Emmanuelle Waubant, University of California, San Francisco who have both been involved with children in California who have “mysterious” paralysis. Please investigate how many, if any, of the approximate 25 children in California who appeared to develop “mysterious” paralysis had consumed Levaquin in the days or months prior to paralysis onset.