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
