Citizens Petition- Psychiatric Effects from Fluoroquinolone Toxicity

Citizens Petition- Psychiatric Effects from Fluoroquinolone Toxicity

Sep 14 2014


September 8, 2014, Dr. Charles Bennett,
University of South Carolina, submitted a Citizen Petition to Dr. Margaret
Hamburg, FDA Commissioner, asking for the following Black Box Warning regarding
Fluoroquinolone Psychiatric Adverse Events:

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.

Additionally, the Citizen Petition requests
that a new heading, “Psychiatric Effects,” be added to the label in the
“Warnings and Precautions” section.

The Citizen Petition also requests that the
following specific Psychiatric Adverse Events be listed on the
label:

Feeling abnormal, loss of consciousness,
disorientation, agitation, delirium, depressed level of consciousness, amnesia,
coma, disturbance in attention, panic attack, memory impairment, and
nervousness.

The Quinolone Vigilance Foundation supports
the below Citizen Petition and we urge the FDA to require these changes
immediately given the seriousness of Psychiatric Adverse
Events.



September 8, 2014
Dockets Management Branch

U.S. Food and Drug Administration

Department of Health and Human Services

Room 1061, HFA-305

5630 Fishers Lane

Rockville, MD 20857

CITIZEN PETITION

RE: Licensed Name: Levaquin

Active Ingredient: Levofloxacin

NDA 020634

Manufactured by Johnson & Johnson (Janssen Pharmaceudicals)

License Date: 12/20/1996


Southern Network on Adverse Reactions (SONAR), submits this Citizen Petition (Petition) under section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act (FDCA) (21 U.S.C. 355(o)(4)) and 21 C.F.R. 10.30. SONAR requests that the Commissioner of the Food and Drug Administration (FDA) require changes in the professional labeling for Levaquin in order to specify a more accurate benefit/risk profile for this antibiotic.

A. ACTION REQUESTED


This Petition requests that the FDA change the professional labeling for Levaquin under Section 505(o)(4) of FDCA or other appropriate FDCA section(s), in response to new safety information. This action will also strengthen the quality of the Levaquin science base and decisions based on it.

Specifically, we request the following changes to the Levaquin label:

1. Require additional Psychiatric Adverse Events to the Levaquin label



It is requested that the following Levaquin Psychiatric Adverse Events be added to the drug label:

Feeling abnormal, loss of consciousness, disorientation, agitation, delirium, depressed level of consciousness, amnesia, coma, disturbance in attention, panic attack, memory impairment, and nervousness.


2. Require a "Psychiatric Effects" heading under "Warnings and Precautions"


It is requested that a specific "Psychiatric Effects" heading be added under the "Warnings and Precautions" section of the Levaquin label rather than listing Levaquin Psychiatric Adverse Events under the "Central Nervous System Effects" heading, as is currently done. It is requested that the following "Psychiatric Effects" section be added to the Levaquin label.

Psychiatric Effects

Serious psychiatric events including,

toxic psychoses, restlessness, anxiety, confusion, hallucinations, paranoia, depression, nightmares, insomnia, suicidal thoughts or acts, feeling abnormal, loss of consciousness, disorientation, agitation, delirium, depressed level of consciousness, amnesia, coma, disturbance in attention, panic attack, memory impairment, and nervousness 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.
 
3. Require the following Psychiatric Adverse Events to the Black Box Warning


It is requested that the following language regarding Psychiatric Adverse Events be added to the current Black Box Warning on 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.
 
B. STATEMENT OF GROUNDS



3 .
Statement of Grounds for Requested Action 1: Add additional Psychiatric Adverse Events to the Levaquin label

The following table lists Levaquin Psychiatric Adverse Events from the FAERS data. The highlighted symptoms are serious Psychiatric Adverse Events, but are not listed on the Levaquin label under "Warnings and Precautions." It is requested that these additional Psychiatric Adverse Events be added to the Levaquin label.
Levaquin FAERS Psychiatric Adverse Events
Compared with the Current Levaquin Label





Adverse Event: Insomnia
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: 4.1%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"? Yes

Adverse Event: Anxiety
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: 3.0%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: Yes



Adverse Event:Depression
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: 2.7%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"? Yes



Adverse Event:Confusional state
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: 2.2%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"? Yes



Adverse Event:Feeling abnormal
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: 1.7%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: No



Adverse Event:Loss of consciousness
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: 1.4%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: No



Adverse Event:Hallucination
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: 1.3%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"? Yes



Adverse Event:Disorientation
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .8%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: No



Adverse Event:Nightmare
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .8%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: Yes



Adverse Event:Agitation
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .7%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"? No



Adverse Event:Delirium
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .7%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: No



Adverse Event:Depressed level of consciousness
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .7%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"? No



Adverse Event:Psychotic disorder
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .7%

Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"? Yes


Adverse Event:Amnesia
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .6%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: No



Adverse Event:Coma
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .6%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: No



Adverse Event:Disturbance in attention
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .6%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: No



Adverse Event:Panic attack
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .6%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: No



Adverse Event:Memory impairment
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .5%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: No



Adverse Event:Nervousness
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .5%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: No



Adverse Event:Suicidal ideation
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .5%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: Yes


Adverse Event:Restlessness
% of Levaquin FAERS Reports Containing this Adverse Event 11/1997 – 6/2012: .5%
Is this Adverse Event on the Current Levaquin Label under "Warnings and Precautions"?: Yes


Statement of Grounds for Requested Action 2: Add a "Psychiatric Effects" heading under "Warnings and Precautions"

Psychiatric Adverse Events are not currently listed under a specific "Psychiatric Effects" heading under "Warnings and Precautions" on the Levaquin label. Instead, Levaquin Psychiatric Adverse Events are currently embedded under the label heading, "Central Nervous System Effects" as illustrated below.

"5.6 Central Nervous System Effects

Convulsions, toxic psychoses, increased intracranial pressure (including pseudotumor cerebri) have been reported in patients receiving fluoroquinolones, including LEVAQUIN® . Fluoroquinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, and, rarely, suicidal thoughts or acts…." (Drugs@FDA, 2014)

Because Levaquin Psychiatric Adverse Events are serious and have a significant impact on quality of life, they deserve a specific heading under the "Warnings and Precautions" section of the label. It is requested that a specific "Psychiatric Effects" heading be added under "Warnings and Precautions."

Statement of Grounds for Requested Action 3: Add a Psychiatric Adverse Events Black Box Warning

As described in the October 2011 FDA "Guidance for Industry, Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling" document:

"A boxed warning is ordinarily used to highlight for prescribers… an adverse reaction so serious in proportion to the potential benefit from the drug…that it is essential that it be considered in assessing the risks and benefits of using the drug" of if "there is a serious adverse reaction that can be prevented or reduced in frequency or severity…" ("Guidance for Industry," FDA, 2011, pg 11, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075096)

Consistent with this FDA Guidance regarding when to add a Black Box Warning to a drug label, Levaquin Psychiatric Adverse Events are serious, may have a significant impact on quality of life, and may be prevented or reduced if physicians and patients have prominent warning through a Black Box. Levaquin Psychiatric Adverse Events, including, toxic psychoses, hallucinations, paranoia, suicidal thoughts or acts, loss of consciousness, delirium, depressed level of consciousness, amnesia, coma, and memory impairment are all serious in that the risk of experiencing these potentially life-threatening symptoms do not outweigh the benefit when Levaquin is used for FDA-
approved routine infections. These Adverse Events, therefore, meet the FDA definition of requiring a Black Box Warning.

Physicians should be adequately warned about these serious Levaquin Psychiatric Adverse Events in order to

provide best practice medicine and patients should be adequately warned about these serious Levaquin Psychiatric Adverse Events in order to provide informed consent. It is requested that a Black Box Warning regarding Psychiatric Adverse Events be added to the Levaquin label.
Additional Grounds for Requested Actions

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)?"




N=94

% Reported




Anxiety:
72%


Depression:
62%


Insomnia:
48%


Panic attacks:
37%


Brain fog and/or cognitive impairment:
33%


Depersonalization and/or derealization:
29%


Thoughts of suicide:
24%


Psychosis and/or hallucinations:
22%


Nightmares and/or abnormal dreams:
21%


Impaired memory:
21%


Emotional outbursts (crying/giggling) and/or mood swings:
17%


Paranoid and/or fearful:
10%


Agitation:
9%


Attention deficit and/or lack of concentration:
9%


Sensation of impending doom:
7%


Difficulty reading and/or doing math:
7%


Confusion:
7%


Mania and/or hyperactivity:
6%


Rage and/or temper flares:
5%


C. ENVIRONMENTAL IMPACT

Nothing requested in this petition will have an impact on the environment.

D. ECONOMIC IMPACT

Not applicable at this time.

E. CERTIFICATION

The undersigned certifies, that, to the best knowledge and belief of the undersigned, this Petition includes all information and view on which the Petition relies, and that it includes representative data and information know to the Petitioner, which are unfavorable to the Petitioner.

Respectfully yours,

Charles Bennett, M.D., Ph.D., M.P.P.

Center for Medication Safety and Efficacy

Southern Network on Adverse Reactions (SONAR),

South Carolina College of Pharmacy/USC Campus

715 Sumter Street, Suite 311-L

Columbia SC 29208

803-777-2289-office

803-777-2820- fax