1. health and fitness
2. disease

 Treatment of Pneumonic Plague: Medical Utility of Ciprofloxacin
Briefing Document
Advisory Committee Meeting of the Division of Anti-Infective Products
the US Food and Drug Administration
April 3, 2012
Division of Microbiology and Infectious Disease
NIH/NIAID
Bethesda, Maryland 20892
Issued March 2, 2012
THIS DOCUMENT IS AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT
REDACTION.
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Table of Contents
LIST OF IN-TEXT TABLES .............................................................................................................. 4 LIST OF IN-TEXT FIGURES ............................................................................................................. 5 LIST OF APPENDICES ...................................................................................................................... 6 LIST OF ABBREVIATIONS .............................................................................................................. 7 EXECUTIVE SUMMARY .................................................................................................................. 9 1 INTRODUCTION ..................................................................................................................... 10 1.1 1.2 1.3 1.4 2 PHARMACOLOGICAL CLASS ................................................................................................................. 10 PROPOSED INDICATION AND DOSAGE AND ADMINISTRATION .................................................................... 10 OBJECTIVES OF THE BRIEFING PACKAGE ................................................................................................ 11 REGULATORY HISTORY ...................................................................................................................... 11 PNEUMONIC PLAGUE .................................................................................................................. 11 2.1 HUMAN CLINICAL DISEASE AND UNMET MEDICAL NEED .......................................................................... 12 2.2 MORBIDITY AND MORTALITY ASSOCIATED WITH PNEUMONIC PLAGUE ....................................................... 13 2.2.1 1905 Treatise on Plague ......................................................................................................... 14 2.2.2 1924 Los Angeles Epidemic .................................................................................................... 16 2.2.3 1926 Treatise on Pneumonic Plague ...................................................................................... 16 2.2.4 Plague: a manual for medical and public health workers ...................................................... 17 2.2.5 Radiographic Findings in Untreated Pneumonic Plague ....................................................... 23 2.2.6 Summary of Untreated Clinical Course of Pneumonic Plague ............................................... 23 2.3 CURRENT OPTIONS FOR THE TREATMENT OF PNEUMONIC PLAGUE ............................................................ 23 2.3.1 Treatment with Sulfadiazine and Penicillin ............................................................................ 23 2.3.2 Treatment with Sulfadiazine, Sulfamerzine, and Streptomycin ............................................... 25 2.3.3 Treatment with Tetracycline and Streptomycin ...................................................................... 26 2.3.4 Treatment with Chloramphenicol and Doxycycline ................................................................ 27 2.3.5 Summary of Treated Clinical Course of Pneumonic Plague .................................................. 28 2.4 THE AFRICAN GREEN MONKEY MODEL OF PNEUMONIC PLAGUE ‐ COMPARISON OF HUMAN AND ANIMAL (AFRICAN GREEN MONKEY) NATURAL COURSES OF PNEUMONIC PLAGUE .................................................. 29 3 SUMMARY OF CIPROFLOXACIN PHARMACOKINETICS IN THE AFRICAN GREEN
MONKEY MODEL AND TRANSLATION TO HUMAN DOSING ........................................ 32 3.1 METHODS OF ANALYSIS ............................................................................................................... 34 3.1.1 Bioanalytical Methodology for PK Study B126-03 ................................................................. 34 3.1.2 Bioanalytical Methods Supporting Efficacy Study A05-04G .................................................. 34 3.2 ABSORPTION ................................................................................................................................ 35 3.2.1 Absorption After Single Escalating PO Doses Administered in a Multi-Phase Study in African
Green Monkeys (Study B126-03) ............................................................................................ 36 3.3 PHARMACOKINETIC PARAMETERS, BIOEQUIVALENCE AND/OR BIOAVAILABILITY ...................... 37 3.3.1 Single and/or Repeated Dosing in African Green Monkeys (Study B126-03 and A05-04G) .. 37 3.4 TOXICOLOGICAL FINDINGS IN PK STUDY B126-03 ...................................................................... 38 2 of 109
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DISTRIBUTION .............................................................................................................................. 38 METABOLISM ............................................................................................................................... 38 EXCRETION .................................................................................................................................. 39 PHARMACOKINETIC DRUG INTERACTIONS ................................................................................... 39 DOSE SELECTION - CIPROFLOXACIN EXPOSURE IN HUMANS AND THE AGM EFFICACY MODEL .. 39 PHARMACOKINETIC SUMMARY .................................................................................................... 39 SUMMARY OF CIPROFLOXACIN EFFICACY .................................................................... 40 4.1 IN VITRO ...................................................................................................................................... 40 4.1.1 Ciprofloxacin Susceptibility Testing in Y. pestis ..................................................................... 40 4.1.2 In Vitro Hollow-Fiber Infection Model ................................................................................... 42 4.2 IN VIVO ........................................................................................................................................ 42 4.2.1 Efficacy of Ciprofloxacin in African Green Monkeys with Pneumonic Plague ...................... 42 5 SAFETY PROFILE OF CIPROFLOXACIN ............................................................................ 49 6 SUMMARY ............................................................................................................................... 51 7 REFERENCES .......................................................................................................................... 52 3 of 109
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List of In-text Tables
TABLE 1 HUMAN AND AFRICAN GREEN MONKEY NATURAL COURSES OF PNEUMONIC PLAGUE ....................................................... 31 TABLE 2 CIPROFLOXACIN ADME NONCLINICAL STUDIES CONDUCTED TO SUPPORT THE PLAGUE INDICATION .................................... 33 TABLE 3 MEAN PHARMACOKINETIC PARAMETERS FOLLOWING SINGLE OR REPEAT DOES OF CIPROFLOXACIN IN AFRICAN GREEN MONKEYS .......................................................................................................................................................... 36 TABLE 4 IN VITRO SUSCEPTIBILITY OF Y. PESTIS TO CIPROFLOXACIN ............................................................................................ 42 TABLE 5 A05‐04G EFFICACY STUDY DESIGN ......................................................................................................................... 43 TABLE 6 A05‐04G, CIPROFLOXACIN EFFICACY, CHALLENGE DOSE, SURVIVAL, TREATMENT INITIATION AND BACTEREMIA OBSERVATIONS ................................................................................................................................................... 46 TABLE 7 A05‐04G: INCIDENCE OF PROMINENT PATHOLOGY FINDINGS IN CIPROFLOXACIN TREATED AND PLACEBO GROUPS ............... 48 4 of 109
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List of In-text Figures
FIGURE 1 CHEMICAL STRUCTURE OF CIPROFLOXACIN .............................................................................................. 10 FIGURE 2 SIMULATED STEADY‐STATE CIPROFLOXACIN CONCENTRATIONS IN AFRICAN GREEN MONKEYS AND OBSERVED VALUES IN HUMANS FOLLOWING INTRAVENOUS INFUSION ......................................................................... 44 5 of 109
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List of Appendices
APPENDIX A INDEPENDENT PATHOLOGY REVIEW SUMMARY APPENDIX B CIPROFLOXACIN IV PACKAGE INSERT 55 73 6 of 109
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List of Abbreviations
g
L
ADME
AERS
AGM
AUC
AUC0-
BBRC
bpm
brpm
C
CBC
CDC
CFR
CFU
CL/F
CLSI
cm
Cmax
CNS
DAIP
DMID
F
F
F
FDA
g
GLP
h
HIB
HPA
HPLC
HPLC/FLD
IM
IND
inf
IP
IV
kg
LD50
LD99
LRRI
M
microgram
microliter
Absorption, Distribution, Metabolism and Excretion
Adverse Event Reporting System
African Green Monkey
area under the concentration vs. time curve
area under the concentration vs. time curve from time 0 to infinity
Battelle Biomedical Research Center
beats per minute
breaths per minute
Celsius
complete blood counts
United States Centers for Disease Control and Prevention
Code of Federal Regulations
colony forming units
clearance of drug divided by bioavailable fraction
Clinical and Laboratory Standards Institute
centimeter
maximum plasma, serum or blood concentration
central nervous system
Division of Anti-Infective Products
Division of Microbiology and Infectious Diseases
female
Farenheit
fractional bioavailability
United States Food and Drug Administration
gram(s)
United States Food and Drug Administration Good Laboratory
Practices
hour
heart infusion broth
Health Protection Agency
high-performance liquid chromatography
high performance liquid chromatography with fluorescence
detection
intramuscular
Investigational New Drug Application
infusion
intraperitoneal
intravenous
kilogram
median lethal dose
dose required for 99% lethality
Lovelace Respiratory Research Institute
male
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MIC
MIC50
MIC90
mg
min
mL
mm HG
N
NA
NaCl
NCTC
NDA
NIAID
NIH
No.
nm
NR
PIND
PK
PO
q 8 hours
q 12 hours
QC
SD
SDE
SOP
Std dev
TBAB
t1/2
tmax
UK
UNM
US
USAMRIID
Vz
Vz/F
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milligram
minimum inhibitory concentration
minimal inhibitory concentration at which 50% of isolates are
inhibited
minimal inhibitory concentration at which 90% of isolates are
inhibited
milligram
minute(s)
milliliter
millimeters of mercury
number of animals or samples
not applicable
sodium chloride
National Collection of Type Cultures
New Drug Application
National Institute of Allergy and Infectious Diseases
National Institutes of Health
number
nanometers
not reported
Pre-Investigational New Drug Application
pharmacokinetic
per os (orally)
every 8 hours
every 12 hours
quality control
standard deviation
single dose escalation
standard operating procedure
standard deviation
tryptose blood agar base
half-life
time to maximum plasma concentration
United Kingdom
University of New Mexico
United States
United States Army Medical Research Institute of Infectious
Diseases
terminal phase volume of distribution
terminal phase volume of distribution adjusted for bioavailability
Yersinia pestis
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Executive Summary
This document was prepared by the Division of Microbiology and Infectious Disease
(DMID) of the National Institute of Allergy and Infectious Disease (NIAID), National
Institutes of Health (NIH) for Pre-IND 113289. The document is intended to provide
information in preparation for the Center for Drug Evaluation and Research AntiInfective Drugs Advisory Committee Meeting on April 3, 2012, during which DMID will
make presentations to discuss:



The efficacy of ciprofloxacin therapy for pneumonic plague
Nonclinical pharmacokinetics of ciprofloxacin and translation to human
dosing
Ciprofloxacin safety and the benefit/risk of ciprofloxacin treatment of
pneumonic plague
Pneumonic plague as a naturally occurring disease is extremely rare in the United States
as well as endemic areas worldwide, but is the likely manifestation of Yersinia pestis if
employed as a biological weapon. The effective treatment of pneumonic plague with
ciprofloxacin was successfully established using the non-human primate animal model.
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Intrroduction
The Diviision of Antii-Infective Prroducts of th
he United Sttates (US) Foood and Druug
Administtration (FDA
A) is conveniing an Advissory Commiittee meetingg on April 3,, 2012 to
discuss reegulatory co
onsiderationss surroundin
ng the use off ciprofloxaciin for the treeatment
of pneum
monic plaguee. Pursuant to
t a marketin
ng authorizaation applicaation for ciprrofloxacin
for the treatment of pneumonic
p
plague,
p
the DAIP
D
has reqquested a meeeting for whhich
DMID haas prepared this
t briefing
g document addressing
a
thhe followingg:



The
T efficacy of ciprofloxaacin in the trreatment of ppneumonic pplague in thee African
Green
G
Monkeey (AGM) model
m
of pneu
umonic plaggue.
The
T relevancee of the dosee of ciproflox
xacin used inn the efficaccy study connducted in
th
he AGM model to human
n exposure.
The
T safety profile of cipro
ofloxacin.
1.1 Ph
harmacolo
ogical Classs
Ciproflox
xacin is a synthetic fluorroquinolone antibacteriaal agent that exhibits a w
wide
spectrum
m of bactericiidal activity against both
h Gram-posittive and Graam-negative
pathogen
ns including Yersinia pesstis. Chemiccally, ciproflloxacin is 1--cyclopropyll-6fluoro-1,4-dihydro-4-oxo-7-(1-piiperazinyl)-3
3-quinolineccarboxylic accid. Its empirical
formula is
i C17H18FN
N3O3. The molecular weiight of ciproofloxacin is 3331.4; its struucture is
shown in
n Figure 1.
Figure 1 Chemical
C
Stru
ucture of Ciprrofloxacin
Ciproflox
xacin is currrently approv
ved and mark
keted in the United Statees and severral parts
of the wo
orld to treat specific
s
infeective conditiions, such ass acute sinussitis, acute
exacerbaation of chron
nic bronchitiis, communiity-acquired pneumonia,, urinary tracct
infection
ns, complicatted intra-abd
dominal infecctions and innhalational aanthrax.
1.2 Prroposed In
ndication and
a Dosag
ge and Adm
ministratiion
The prop
posed indicattion for cipro
ofloxacin is the treatmennt of pneumoonic plague in adult
patients at
a an intravenous dose off 400 mg q 12
1 hours for 14 days. As for other
severe/co
omplicated in
nfections, peediatric patieents (age 1-117) would reeceive an IV dose of
6-10 mg//kg (not to ex
xceed 400 mg/dose)
m
q 8 hours for 100-21 days.
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1.3 Objectives of the Briefing Package
The objective of this briefing document is to present data to support the efficacy of
ciprofloxacin in the treatment of pneumonic plague.
1.4 Regulatory History
A United States Food and Drug Administration/National Institutes of Health (FDA/NIH)
Antibiotic Working Group met in 2001-2002 and discussed the development of
therapeutic options for pneumonic plague and inhalation anthrax, for the general
population. The FDA and NIH selected antibiotics for a potential treatment indication for
pneumonic plague that met the following criteria: had large safety databases, both oral
and intravenous formulations were available, adequate production capacity existed, and
demonstrated utility in special populations; ciprofloxacin is one of the drugs. The
National Institutes of Allergy and Infectious Disease (NIAID) and FDA jointly undertook
a program of animal model development, and pharmacokinetic and efficacy studies to
address this need. In March 2003, at the request of the FDA, the Division of
Microbiology and Infectious Diseases (DMID), NIAID/NIH, established PreInvestigational New Drug Application (PIND) 64,429 to collect communications,
protocols and data for the animal model and testing of antibiotics. In 2003, after the first
natural history study (F03-09G), data was presented to FDA and a treatment trigger was
selected for subsequent antibiotic efficacy studies. Ciprofloxacin efficacy was
successfully tested in this model in 2005. To facilitate FDA’s review of ciprofloxacin for
the treatment indication for pneumonic plague, DMID filed a new PIND (113289) which
is specific for the antibiotic ciprofloxacin.
NIAID filed PIND 113289 to the FDA for consideration as evidence supportive of a label
indication for ciprofloxacin for the treatment of pneumonic plague. As NIAID does not
hold an NDA for this drug, NIAID is not submitting a supplemental new drug
application, but instead is seeking a decision on whether this package will support future
labeling supplement application(s). FDA decision regarding a labeling supplement could
be shared with generic sponsors of ciprofloxacin as was done for doxycycline and
penicillin G for inhalation anthrax (post-exposure) as published in the Federal Register,
November 2, 2001, Notice on “Prescription Drug Products: Doxycycline and Penicillin G
Procaine Administration for Inhalational Anthrax (Post-Exposure).”
2 PneumonicPlague
The goal of this section is to summarize the historical and literature-based evidence for
understanding the correlation of clinical pathogenesis between the AGM model of
pneumonic plague and the human clinical disease.
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2.1 Human Clinical Disease and Unmet Medical Need
Plague is caused by an infection with Yersinia pestis (Y. pestis), a gram negative, bipolarstaining bacillus and member of the family Enterobacteriaceae. The yersinioses are
zoonotic diseases affecting rodents, pigs, birds, and other domestic and wild animals;
humans are only incidental hosts. However, pandemics due to Y. pestis have been
responsible for large losses of human life and profound changes in society over the past
two millennia (Dennis, 2009).
Plague can have several forms. The most common is bubonic plague in which illness
typically begins after a 2- to 7-day incubation period following a bite by an infected flea
that had been feeding on an infected mammal, often a rat (Dennis, 2009; Inglesby 2000).
The bacteria reproduce in regional lymph nodes draining the area of the bite and cause
the nodes to swell in size from 1 to 10 cm in length to form a bubo, which is exquisitely
tender and firm with the overlying skin being warm and stretched. This is usually
accompanied by the sudden onset of fever, chills, weakness, and headache. Some patients
develop skin lesions including papules, vesicles, or pustules distal to the bubo that may
represent sites of flea bites. Patients may not seek care during the first days of the illness,
but when they present clinically, they are typically prostrate and lethargic and may also
be restless or agitated. Such patients usually have fever in the range of 38.5 to 40.0ºC, but
may have higher fever with delirium or, in children, seizures. The pulse rate is typically
increased to 110 to 140 beats per minute (bpm), and there may be hypotension due to
vasodilatation. The liver and spleen may be palpably enlarged and tender. Without
appropriate treatment, shock may develop with a rapidly downhill clinical course
culminating in death 2 to 3 days after the onset of symptoms (Dennis, 2009).
Septicemic plague can arise as a result of rapid replication of Y. pestis in the blood in
early acute cases of bubonic plague or occasionally, it can arise without the development
of a bubo (Dennis, 2009; Inglesby, 2000). It is associated with a higher case-fatality ratio
than bubonic plague, which may be due, in part, to delays in diagnosis and treatment.
Without early intervention, it will produce a systemic inflammatory response that may
lead to disseminated intravascular coagulation, bleeding, organ failure, and irreversible
shock. Purpuric skin lesions are usually found scattered across the extremities and trunk.
At first, they are red but change to dark purple. Blockage of the peripheral vessels in the
acral sites (such as the tips of fingers, toes, ears, and nose) can lead to gangrene; hence
the term “Black Death” as a pseudonym for plague.
The third, most feared manifestation is pneumonic plague. This can be secondary
pneumonia that can arise when Y. pestis reaches the lungs by hematogenous spread from
a bubo or from the bacteremia of septicemic plague (Dennis, 2009; Inglesby, 2000). It is
a malignant pneumonia that is accompanied by sepsis and progresses rapidly to death
without prompt medical intervention. In addition, pneumonic plague is highly contagious
through respiratory droplet spread, especially through close contact with family and
caregivers (Dennis, 2009). Primary pneumonic plague is defined as disease resulting
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specifically from inhalation of infectious Y. pestis respiratory droplets and can be
transmitted from human to human without involvement of fleas or animals (Dennis,
2009; Inglesby, 2000). Respiratory droplet spread results in inhalation of Y. pestis
bacteria directly into the lungs, which could be from the cough of another human with
pneumonic plague, an infected animal, or perhaps, an intentional release in a bioterrorism
event.
Prior to the development of modern antimicrobial agents, pneumonic plague was
considered to have an extremely poor prognosis. In most series of cases from the preantibiotic era, the mortality rate was essentially 100%.7 Earlier treatments for plague
included carbolic acid, antimony sodium tartrate, Bayer 205 (Germanin), electrargol or
collargol (colloidal silver), Eusol (boric acid and chloride of lime), Fonabisit
(formaldehyde sodium bisulfate), tincture of iodine alone and mixed with camphor and
thymol, intravenous (IV) mercurochrome, perchloride of mercury, and urotropin
(hexamethylenetramin). Initial reports gave encouraging results that were not often
duplicated. Various serum, bacteriophage, and vaccine therapies were developed and
tried with similar results (Chun [a,b], 1936).
The United States (US) Food and Drug Administration (FDA) has approved the
following antibiotics as plague treatments, in addition to their other marketed indications:
the aminoglycoside, streptomycin, and the tetracycline class, demeclocycline,
doxycycline, minocycline, and tetracycline. However, streptomycin is infrequently used
in the US and only exists in limited supplies (Louisiana Office of Public Health, 2004).
Tetracycline and doxycycline have been used in the treatment and prophylaxis of plague;
however, there are no controlled studies comparing these agents to aminoglycosides in
the treatment of plague. Although not yet approved for this indication, the
fluoroquinolone class of antimicrobials has demonstrated effectiveness against Y. pestis.
In reviewing the case reports and summaries of observations from patients with
pneumonic plague, one is struck by the great variability in the presentations, though a
consistent clinical course emerges. Fever, especially high fever, is often the first sign.
Cough appears to develop at various times in the course of the illness and may or may not
be productive at first, but typically progresses from producing thin, sometimes bloodtinged, sputum to more profuse production that can be substantially bloody. Usually the
findings on physical examination of the lungs belie the severity of the pneumonia and
prognosis for the patient. Delirium and a staggering walk were observed in many cases.
One thing appears certain, without early initiation of appropriate antibiotic treatment, the
course of the disease is fatal.
2.2 Morbidity and Mortality Associated with Pneumonic Plague
This report has been prepared to provide a brief history of plague and a description of
clinical manifestations of pneumonic plague infection. Cases are described in terms of
clinical signs and symptoms with the time frame of development after infection, as well
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as the histology and radiology examinations. The Centers for Disease Control (CDC) has
confirmed that there are no cases of pneumonic plague that have not been published and
would contribute to this summary (personal communication).
Clinical case descriptions of untreated pneumonic plague can be found in older literature
and provide an overall picture of the clinical course of the untreated Y. pestis infection.
These case descriptions are summarized below.
2.2.1
1905 Treatise on Plague
In 1897, Dr. Poch initially documented (in the German language) the death of Dr. Manser
and his nurse of Bombay, India, and the deaths of Dr. Mueller and a nurse of Vienna,
Austria. These accounts were later translated and published in the 1905 Treatise on
Plague (Simpson, 1905) and are summarized here.
2.2.1.1
Manser case (Bombay, India)
On the first day of his illness, Dr. Manser had a sudden rigor and felt a fever coming on.
Later that day he developed a severe headache, became nauseated and vomited several
times. His limbs ached and he became lethargic. At 2 PM on Day 1, his temperature was
103.4°F, his pulse was 116 bpm, and his respiration rate was 25 breaths per minute
(brpm).
On Day 2, after not getting much sleep, he felt worse except for the aching in his limbs.
His temperature remained elevated at 103.5 to 104.5°F, his pulse was about 110 bmp, and
his respiration rate was approximately 23 brpm throughout the day. The afternoon of
Day 2, he felt a pain at the lower part of his left axilla, but no enlarged or tender lymph
nodes were discernable.
On Day 3 of his illness, after another restless night, he felt very ill. His temperature had
risen to 104.6°F, his pulse was 113 bpm, and his respiration rate was 25 brpm. His tongue
was still moist with a little “fur” toward the back, and his previously described symptoms
persisted. That night he began to cough up watery sero-mucous fluid that contained
minimal amounts of blood. Moist respiratory sounds, reminiscent of early pneumonia,
could be heard on auscultation. Microscopic examination of the sputum revealed many
bacilli that appeared to be Y. pestis, which was confirmed from sputum cultures growing
pure colonies of Y. pestis.
During Day 3 and Day 4 of his illness, Dr. Manser’s condition deteriorated. His
temperature remained around 104°F and expectoration became more profuse. Moist rales
could be heard throughout his chest. Respiration rate measured at 35, increased further to
45 brpm, and his pulse increased to 120 to 135 bpm. Dr. Manser died early the morning
of Day 5.
The evening after the death of Dr. Manser, his nurse became ill and developed symptoms
of pneumonia the following day. She rapidly became worse and died on Day 3 of her
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illness. While her sputum production was not as profuse, she became exhausted much
quicker. Examination and culturing of her sputum revealed the presence of Y. pestis.
2.2.1.2
Mueller case (Vienna, Austria)
Dr. Mueller appeared to have contracted pneumonic plague from a patient who was a
worker in the pathological institute in Vienna, Austria or from one of the nurses who
tended to this patient.
One of the patients at the pathological institute in Vienna, Austria died 4 days after
presenting to the clinic. The patient’s illness was later confirmed bacteriologically to be
pneumonic plague. Two days after the death of this patient, one of the nurses that cared
for the patient became feverish, and Dr. Mueller volunteered to take care of her.
However, that evening (Day 1), Dr. Mueller felt chilled and began to shiver despite the
room being well heated. He had a non-productive cough and some aches in his legs, and
he felt depressed. Dr. Mueller retired for the night without finishing his dinner; he slept
well.
The morning of Day 2 upon visiting the nurse who had become ill, he was reported to be
very pale and fatigued. His pulse was 110 bpm, and although his cough was frequent, it
was still unproductive. Dr. Mueller took a 3-hour nap, after which, his temperature
measured 38.2°C (100.8°F). He then returned to bed. Later that day, he began to
expectorate reddish, thin fluid which was found to contain bacilli consistent with
Y. pestis. His pulse was 120 bpm and his respiration rate was 40 brpm. Coughing became
more frequent with production of copious amounts of reddish sputum. There were no
complaints of pain. Fluid, but not bloody, stools were reported the afternoon of Day 2,
and in the evening (6 PM), his temperature had reached 40.8°C (105.4°F), and he
reported being very thirsty. Digitalis and alcohol were administered. Dr. Mueller refused
an injection of plague serum. He had bouts of delirium but was able to sleep.
On the morning Day 3 of his illness, Dr. Mueller’s conjunctivae were reddened. He was
delirious and spoke incoherently. He produced large amounts of reddish fluid sputum. No
solid food was ingested that day, and a second dose of digitalis and “good quantity” of
alcohol were given. In the afternoon of Day 3, he took morphine for chest pain. Four thin,
non-bloody stools were produced with pain. At 6 PM that evening, his respiration rate
quickened to 59 brpm, and he became cyanotic. Coughing became more frequent with
continued production of bloody sputum. His consciousness was dulled. At 10 PM, his
body temperature dropped to 37.8°C (100.0°F) and while consciousness seemed to get
clearer, restlessness and delirium eventually set in.
At 1 AM on Day 4 of his illness, Dr. Mueller got up and walked with assistance, and
returned to bed and slept. Three hours later, his temperature was 38°C (100.4°F) but
breathing was difficult and cyanosis had increased. At 4:15 AM, a rattling in his throat
was heard and bloody mucus poured from his mouth. He died at 4:30 AM on Day 4.
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1924 Los Angeles Epidemic
Other clinical cases of primary inhalation pneumonic plague from the 1924 epidemic in
Los Angeles, CA have been described by Bogen (Bogen, 1925). Among the 32 cases, he
observed that the primary symptoms of pneumonic plague, in order of frequency, were
fever (37.8 to 41.1°C [100.0 to 106.0°F]), expectoration with blood-stained sputum,
cough, pain in the chest, headache, generalized pains, vomiting, pain in the back and
upper abdomen, malaise, epistaxis, and chilliness without rigor. Primary physical
examination findings, in order of frequency, were large, coarse rales in the chest, thickly
coated tongue, reddened throat, dyspnea, impairment of percussion note over the chest,
restlessness, prostration, delirium, weak rapid pulse, cyanosis, a systolic murmur,
localized adenopathy, conjunctival injection, increased spinal fluid pressure, with signs of
meningismus in the child cases, jaundice, and a macular rash. With the exception of
2 patients, all died. Greater than half of these patients received IV or intraperitoneal (IP)
injections of mercurochrome, including the 2 survivors.
A summary by Link (Link, 1955) in Chapter VIII of “A History of Plague in the United
States of America” provides additional information about this epidemic.
2.2.3
1926 Treatise on Pneumonic Plague
In 1926, Wu Lien-Teh produced “A Treatise on Pneumonic Plague” for the League of
Nations. (Wu Lien-Teh, 1926). He was a highly regarded expert in the field because of
his extensive experience with pneumonic plague during the epidemics that occurred in
Manchuria. Regarding the incubation period for pneumonic plague he wrote, "In the
majority of cases, the incubation period is under 5 days; nevertheless,...6 days is frequent
enough to deserve serious attention. Longer periods are very rare.... An incubation of
less than 2 days is comparatively rare.... We doubt if such ever occurs."
In Chapter V, Section II: Symptomatology, he provides the following summary of the
clinical features of pneumonic plague from personal and reported observations:
"The onset of the disease is sudden and often marked by rigor. The first stage is
characterised by the presence of general signs only; cough is most often still
absent; when present, it is usually dry. The prominent symptoms during this
period are severe headache, some nausea and vomiting, vertigo and general
malaise. Both respiration and pulse show an increased rate; the pulse is early
impaired in quality. The temperature, which is but slightly raised at the beginning
of the illness, rises steadily during the first stage. Most of the symptoms present
during this period appear to be toxic in nature and are best explained by an
influence upon the central nervous system. Inasmuch as, during this period no
bacteremia is present, it is feasible to assume that some toxemia exists early in
the disease.
The beginning of the second stage is manifested by the appearance of cough or if this is already present - by that of expectoration. The cough is dry and seldom
troublesome at first, when continuous may exhaust the patient. The sputum
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shows at first no characteristic appearance, being mainly frothy. Soon, however,
there is an admixture with blood, leading to a uniform bright pink or red hue.
Now the sputum may be either thin, sometimes frothy or of more syrup-like
consistency; but the degree of viscosity typical for croupous pneumonia is not
reached. The quantity of bloody sputum varies greatly from mere streaks of red
to ounces of deep-red blood comparable to that seen in hemorrhage in phthisis
(tuberculosis).
During the first stage, few if any signs may be detected over the lungs; now
symptoms of pneumonia become evident. The comparative insignificance of
physical signs in the lungs even in the second stage is in marked contrast to the
serious condition of the patient.
The respiration increases in frequency, dyspnea grows more and more marked
and the face soon assumes a cyanotic hue. The temperature, which reaches its
height at the beginning of the second period, remains high, with little or no
matutinal [early in the day] remissions. The pulse is soft, increases in frequency
and deteriorates in quality from hour to hour.
The patient becomes dull and assumes an anxious look. Sometimes coma or
delirium is present, but usually consciousness is not lost until the very last.
Ataxic gait and incoordination of speech are frequent.
Death occurs from heart failure. Sometimes there is a marked stage of agony
characterized either by more or less protracted coma and symptoms of lung
edema or by restlessness and active delirium. Often death is quite sudden,
brought about by some slight exertion. In the Manchurian outbreaks especially,
such a sudden painless death was the rule, and corpses were found in all sorts of
positions.”
In this 1926 treatise, Wu Lien-Teh summarized 41 reports on the duration of illness (refer
to Table LVIII in the source reference) (Wu Lien-Teh, 1926). The average duration of
illness observed was 1.8 days with the longest duration being 9 days.
2.2.4
Plague: a manual for medical and public health workers
In a text book collaboration by Wu Lien-Teh, et al. (Chun [b], 1936), the clinical courses
of 9 individuals with pneumonic plague during the pre-antibiotic era are described; many
of these cases were initially described in his 1926 treatise (Wu Lien-Teh, 1926). These
cases are presented here.
2.2.4.1
Case 1
One case of the Manchurian pneumonic plague epidemic of 1921 was that of a female,
“Mrs. S”, 28 years of age. Mrs. S was the sister-in-law of the first plague patient
appearing in Harbin, China on 22 Jan 1921; she was 1 of 4 contacts found living in the
same room as this patient (the others were the mother, sister and male friend). It was not
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expected that Mrs. S would have been in close contact with the patient; however, the
whole family was living in one room (12 x 12 square feet).
All contacts were isolated in the hospital quarantine compound, and being the first cases,
were examined with special care. On Day 1, Mrs. S was active and loquacious, opposing
strongly to the idea of her being deprived of her freedom. On Day 2, she still demanded
to be set free, although the other 3 contacts took being quarantined more
“philosophically”. On Day 3, Mrs. S was quieter and happy when persuaded that, if all
went well, on Day 5, the family could go home.
On the afternoon of 26 Jan (Day 5 after contact with the plague patient), Mrs. S felt
chilled and unwell. Her pulse was 108 bpm, respiration rate 20 brpm, and body
temperature 100.0°F. The next morning, she complained of not having slept well, her
pulse increased to 118 bpm, respiration rate to 24 brpm, and body temperature to
101.5°F. Her whole condition seemed to have changed overnight. Her face was pale and
drawn, she looked weak and anxious, and her head ached badly. Mrs. S was now
separated from the other 3 contacts, and she was unconcerned with conversation.
Toward the evening, symptoms became worse; slight cough and sputum developed, and
some pain was felt on the left side of the chest. Her pulse was 120 bpm, respiration rate,
30 brpm and temperature, 102°F. Physical signs in her lungs were slight. Her urine was
cloudy but no albumin was detected. Within the next 2 hours, blood streaks had appeared
in her sputum, which had now increased in quantity. Pasteurella pestis (now known as
Y. pestis) were identified. At this time, the patient’s pulse increased to 130 bpm,
respiration rate to 36 brpm, and temperature, 102.5°F. Water and medicine were
requested by the patient to ease her headache and increasing tightness of chest. That
evening (10 PM), examination of the peripheral blood showed plague bacilli. General
symptoms increased in severity, and the patient became very restless and died in the early
morning of the following day, which was Day 6 from the time of contact with her
brother-in-law (the first plague patient). The other three contacts with the first patient
remained healthy.
2.2.4.2
Case 2
A second case was that of “Dr. YTM”, a male, 24 years of age. Dr. YTM was in charge
of district inspection squads from 11 Feb 1921. Duties included visiting suspected
plague-ridden houses, bringing back sputum, and making spleen punctures of corpses. He
was a thorough worker, conscientious, and always wore proper masks.
On 17 Feb 1921, Dr. YTM felt unwell but continued work as usual. He attended to
30 people that day, but toward the evening, he began to feel unwell. That evening, he had
a flushed face, pulse of 120 bpm, respiration rate of 22 brpm, and temperature of 102°F,
and complained of severe pain in head and back. He had an injected cornea with
photophobia. Dr. YTM was conscious and aware of his fate. Electrargol or collargol
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(colloidal suspension of silver cations) was injected (10 cc), along with aspirin. He slept
poorly that night.
The next day (Day 2), the patient appeared drowsy. His pulse was 124 bpm, respiration
rate, 30 brpm, and body temperature, 102°F. His sputum was blood-stained with pure
growth of Y. pestis obtained. He was still coherent and rational but had to be roused.
Antipest serum (40 cc) and electrargol (10 cc) were injected subcutaneously. Hours later,
although delirious, he could recognize people. That evening, his pulse increased to 130
bpm, respiration rate to 36 brpm, and temperature, 103°F; more blood-stained sputum
was produced. Another 50 cc of antipest serum was injected with no apparent effect.
On Day 3 of infection, his pulse was weaker at 150 bpm, respiration rate was 40 brpm,
and temperature, 102.5°F. Tubular breathing and rales were recorded, along with swollen
legs and marked delirium. Cough was minimal, but large amounts of sputum were
observed with much blood. A third injection (IV) of antipest serum (80 cc) was
administered. At midnight on Day 4, Dr. YTM was very delirious with increased sputum
with much blood. His urine was scanty and of dark color with trace of albumin. The
following morning (Day 5), he was found in the adjoining room dead, lying over the bed
with legs touching the ground.
2.2.4.3
Case 3
The third case was that of “Dr. M”, a European male, 43 years of age. Of note, Dr. M had
lived through the bubonic plague epidemic at Tongshan, China in 1908. Dr. M
accompanied Dr. Haffkine on a visit to a plague ward in Russia Jan 1911. Neither
physician wore a protective mask. During this visit, Dr. M examined the chest of a plague
patient via percussion and auscultation. Four days later, he complained of headache with
fever (temperature 101°F) and fast pulse. Cough and sputum appeared next day. Two
doses of antiplague serum (230 cc and 180 cc) were given with no apparent effect. Blood
soon appeared in sputum, and when examined, plague bacilli were found in large
quantities. The patient rapidly became weakened, as his temperature rose to 103°F, pulse
to 140 bpm, and respiration rate to 40 brpm. Dr. M died 6.5 days after the visit to the
plague ward.
2.2.4.4
Case 4
In March 1921, “Mrs. L”, 17 years of age, lost her husband due to plague. She was then
quarantined in railway wagon. For 6 days she had a normal pulse and temperature, and
appeared free of infection. She was released to go home, which was 0.5 miles away from
the quarantine wagon. Soon after arriving home, she became ill and was admitted to the
hospital. She presented with no cough or sputum. However, the following day, she
experienced much cough with bloody sputum, in which Y. pestis was confirmed to be
present. Her pulse was measured at 130 bpm, respiration rate at 36 brpm, and
temperature, 103°F. Thirty hours after admission, Mrs. L was pronounced dead. Postmortem results showed pneumonia in the lungs.
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Case 5
On 22 Mar 1921, a few days after losing her husband to plague, “Mrs. F”, 31 years of age
and pregnant with her fourth child, was admitted to the hospital with fever (102°F) and
fast pulse (120 bpm) and respiration rate (30 brpm). This was the second or third day of
her illness. She experienced much coughing with blood-stained sputum in which plague
bacilli were observed. She had a generally weak condition with dark urine without the
presence of albumin.
Later the same day, Mrs. F gave birth to a deceased full-term female fetus; the placenta
passed without trouble. Mrs. F’s general symptoms became worse, and the patient died
early the next morning. Post-mortem examination of Mrs. F showed definite signs of
plague pneumonia in her lungs. The placenta also showed plague bacilli, and although
organs of the fetus appeared normal, plague bacilli were isolated from them.
2.2.4.6
Case 6
“Dr. S”, a Russian male, 33 years of age, was in charge of house-to-house inspection in
Harbin Railway area from 20 Feb 1921. He was admitted to the hospital on 18 Mar 1921,
complaining of fever (temperature 39.6°C [103.3°F]) and pain over the right side of
chest. His pulse was 102 bpm and respiration rate, 26 brpm. The patient was conscious
and thirsty. On percussion, some dullness below right scapula was recorded, and no rales
were heard on auscultation. The following day (Day 2), his pulse was 110 bpm,
respiration rate 34 brpm, and temperature 39.7°C (103.5°F). Some delirium was
experienced, and on auscultation, large crepitant rales were heard over a dull area. The
patient received an injection of camphor with 80 cc serum, along with methylene blue
(0.03 g, 6-times daily for 2 days). That evening, his pulse became faster and weaker, and
arrhythmia was reported. Cough developed with sputum containing an abundance of
plague bacilli.
On Day 3, the patient’s temperature ranged from 40.4 to 40.6°C (104.7 to 105.1°F). He
complained of a pain below the right collar bone. The patient experienced nausea and
vomiting. Dr. S was conscious and could answer questions intelligently, albeit slowly;
however, his hearing was impaired and he could not walk properly. His appearance was
one of exhaustion, with a reddish-violet face and blue nails. Pulse was measured over 150
bpm and respiration rate greater than 50 brpm. Anti-diphtheria serum was given (5,000
units) along with camphor oil. At 7 PM that evening, marked cyanosis, irregular
breathing, and increased cough with much sputum and blood, were observed. The patient
became unconscious and died at 3 AM, the morning of Day 4.
2.2.4.7
Case 7
Case 7 involves 3 refugees from Irkutsk, Russia. All three, looking ill and starved, were
admitted to Suspect Block (presumably where suspect cases were held for observation)
on 8 Feb 1921. One of the 3 spat blood and died 5 days later (13 Feb) with suspicious
signs of plague. A second refugee complained of plague-like symptoms and was put in a
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plague ward. He died on 17 Feb 1921; however, swabs from his throat and sputum
repeatedly failed to show Y. pestis.
The third refugee, a 35-year-old male, spent 11 days in plague ward without a mask and
without signs or symptoms of infection. He subsequently volunteered as an attendant in
the plague ward with inconsistent use of a protective mask. After 3 weeks, he showed
signs of plague with fever, fast pulse, and respiration rate of 30 brpm. Soon after, he
produced bloody sputum, in which plague bacilli were identified. There were also clinical
signs in his lungs. Eusol (120 cc IV) was injected. The patient quickly became
unconscious and breathing was stertorous. Within 24 hours of symptoms first appearing,
the patient died. Therefore, former contact with plague patients did not produce
immunity.
2.2.4.8
Case 8
On 15 Mar 1921, a male, 32 years of age was admitted for care, presenting with typical
plague symptoms (fever, fast pulse and quickened respiration). His sputum, initially
scanty, produced Y. pestis. The patient retained his appetite and remained stable for days.
His sputum was examined every 2 days and resulted in small numbers of Y. pestis.
Subsequent specimens were darker and mucopurulent with Y. pestis was always present.
The patient was secured in a special ward, as his recovery appeared hopeful.
On 21 Mar (5 days after admission), the patient received 60 cc serum. Fever remained
high, ranging from 102 to 102.5°F, pulse increased, 114 to 120 bpm, and respiration rate,
24 to 36 brpm. Some rales in both lungs were documented, as was albumin in his urine.
Over the next 2 days, his condition worsened; pulse quickened to 140 bpm and
respiration rate, nearly 50 brpm. The patient died the next day, 9 days after admission
into the plague ward. This was the longest survival time on record following Y. pestis
infection in the pre-antibiotic era. Post-mortem examination showed marked pleuritis and
pneumonia; plague was confirmed.
2.2.4.9
Case 9
The ninth case is that of a 21-year-old male rat catcher who arrived in Lungyen (Fukien
Province, Manchuria) on 18 Jul 1935 (Chun [a], 1936). For 10 days he trapped rats and
searched for plague cases without success. Therefore, Y. pestis infection seemed unlikely.
In addition, this man participated in the fumigation of 4 houses with sulphur gas.
Collection and transportation of dead rats was always performed with the proper
protection.
On July 28, 10 days after his arrival to this region, he complained of pain in the right side
and in the back of the chest with a noted slight fever. The following day (Day 2), his
pulse was 92 bpm and temperature, 102°F. The patient was not feeling well and suffering
from severe backache, but without cough or headache. On the morning of Day 3, cough
and bloody, frothy sputum appeared. Microscopic examination of sputum smears showed
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many plague bacilli – some in chain formation. Toward evening, both cough and sputum
increased with the sputum becoming liquid. Tightness and pain in his chest had become
worse, and severe headache was reported.
On Day 4, the patient became delirious. Expectoration of liquid blood-stained sputum
continued, and his pulse rose (110 to 120 bpm) and temperature reached as high as
105°F. The patient died the morning of Day 5.
2.2.4.10 Summary
Based on these cases, Chun provided a description of a typical clinical course for a
patient with pneumonic plague which is described below (Chun [a], 1936).
From the onset of illness, the patient suffering from primary plague pneumonia will show
signs of serious infection and feel suddenly unwell. He/she may be prostrated with mental
confusion, severe headache, pain in the back and pain at the site of the bubo (if present),
chills or rigor, a coated tongue, injected conjunctiva, and loss of muscle coordination for
walking to the point of staggering. There may be vomiting and/or diarrhea (sometimes
bloody). Within 24 to 36 hours, body temperature will be raised to 40.0°C (104.0°F) or
higher and pulse, quickened to 110 to 130 bpm. The patient may have an anxious
expression. The face will often be flushed and bloated and with time assume a dark,
dusky hue. The mucous membranes of the mouth and the fauces typically will be
congested and cyanotic. Usually, the spleen will not be palpable and lymphatic glands,
not enlarged. Leukocytosis may be absent.
In general, the patient will complain of pain and a restricted feeling in the chest that is not
severe. Cough and dyspnea develop. The cough is usually easy and not painful. At first,
the cough is dry and sputum is scanty, but subsequently, the sputum becomes more
abundant and blood-tinged, and later, it becomes thinner and frothy with a bright red
color. At this point, the sputum is highly contagious as it contains almost a pure culture of
Y. pestis.
The physical signs in the lungs are often slight, even in the advanced stages. In some
cases, local areas of dullness on percussion may be observed. Rales may be present on
auscultation but are not frequently heard except just before death when numerous rales
can be heard due to pulmonary edema. A dry pleuritic rub may be heard at the side of the
chest. The heart is usually slightly dilated on the right side; heart sounds are fast and
become more feeble. The second pulmonary sound may be accentuated early on but this
character is soon lost.
In the later stages of the illness, the respirations become increased with marked dyspnea
and gasping for breath several hours before death. Cyanosis is common and ecchymoses
appear in different parts of the body. The pulse becomes more rapid, soft and feeble until
it cannot be felt. Body temperature may decline to or below normal near the end of life.
The patient is usually delirious (even may be inappropriately cheerful) or comatose.
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Immediately before death there may be profuse hemoptysis with bloody froth seen at
nostrils. Death results from cardiac paralysis and exhaustion. Patients sometimes
succumb after slight physical exertion, such as sitting up in bed or being moved. Death
occurs 2 to 3 (rarely 4) days after infection.
2.2.5
Radiographic Findings in Untreated Pneumonic Plague
Alsofrom, et al. (Alsofrom, 1985) reported radiographic findings of 9 patients with
probable (n = 5) and confirmed (n = 4) secondary pneumonic plague, in addition to
findings from 28 patients with bubonic plague and 5 patients with septicemic plague.
This summary focuses on the pneumonic plague cases.
All 9 pneumonic plague patients revealed alveolar pulmonary infiltrates, 8 of which were
bilateral. In general, the infiltrates were non-segmental and within the alveoli with a
propensity for the lower lobes. Mediastinal or hilar adenopathy, as well as pleural
effusions, were observed in both bubonic and pneumonic plague patients. Five (55.6%;
5/9) pneumonic plague patients had cervical adenopathy and one had supraclavicular
adenopathy; in contrast, only 2 of the 27 (7.4%) bubonic plague patients with a
radiography assessment had cervical involvement.
A total of 3 (33.3%; 3/9) pneumonic plague patients died. Treatment received by these
patients was not reported; therefore, it is difficult to draw conclusions from this report.
2.2.6
Summary of Untreated Clinical Course of Pneumonic Plague
In reviewing these case reports and summaries of observations from patients with
pneumonic plague, one is struck by the great variability in the presentations though a
consistent clinical course emerges. Fever, especially high fever, is often the first sign.
Cough appears to develop at various times in the course of the illness and may or may not
be productive at first, but typically progresses from producing thin, sometimes bloodtinged, sputum to more profuse production that can be substantially bloody. Usually the
findings on physical examination of the lungs belie the severity of the pneumonia and
prognosis for the patient. Delirium and a staggering walk were observed in many cases.
One thing appears certain, without early initiation of appropriate antibiotic treatment, the
course of the disease is fatal.
2.3 Current Options for the Treatment of Pneumonic Plague
Several early generation antibiotics have been used in the treatment of pneumonic plague
and reported in the literature. Several cases of pneumonic plague where antibiotic
treatment was administered are described below.
2.3.1
Treatment with Sulfadiazine and Penicillin
A report by Munter describes a laboratory worker infected with Y. pestis and successfully
treated with sulfadiazine (Munter, 1945).
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The laboratory worker “Dr. JH”, who worked with a virulent strain of Y. pestis at the
Plague Investigation Station of the US Public Health Service in San Francisco, CA
became ill on 31 May 1944. Approximately, 1 year prior, he had received 5 injections of
plague vaccine over 6 months due to the risk of infection through his research. This
vaccine was prepared from virulent Y. pestis which had been chemically killed.
The initial onset of malaise, chills and hacking cough was accompanied by fever (104°F)
and blood-tinged sputum. He was admitted to the hospital on Day 2 of onset, complaining
of malaise, pain in the chest (low down on the right side), and a frequent, non-productive
cough. He was aware but confused and disoriented. His temperature was 104°F, pulse
was 100 bpm, respiratory rate was 26 brpm, and his blood pressure was 110/70 mm Hg.
His throat was reddened, and no cervical, axillary, or inguinal adenopathy was present.
There was an area of impaired resonance at the back base of the right lung. Breathing was
normal except for fine scattered rales, and there was a faint systolic murmur at the apex
of the heart. White blood cell count was 18,000 with 88% neutrophils and 12%
lymphocytes. Examination of his sputum within 24 hours of admission revealed large
numbers of bacteria compatible with Y. pestis, which were subsequently confirmed.
Treatment with sulfadiazine was started immediately beginning with 12 g orally (per os
[PO]) within the initial 20 hours and 1 g every 4 hours thereafter. After 24 hours, blood
levels of sulfadiazine were 4 mg/mL; therefore, 2.5 g of sodium sulfadiazine was
administered IV, and the oral dose was increased to 2 g every 6 hours. On Day 4
following onset of symptoms, penicillin (100,000 units/day) was started and given every
24 hours for the next 3 days. There was no evidence that penicillin altered the course of
infection.
Over the first 4 days, his temperature ranged from 102.2 to 106.8°F. Coughing continued
but was not violent and produced small amounts of sputum. During the first 6 days, the
patient experienced delirium and wildly irrational behavior for which he was given
morphine and scopolamine. On Day 6, body temperature decreased with signs of
improvement. His cough was milder and less productive; at this time, no plague bacilli
were cultured from the sputum. On Day 8, his temperature returned to normal and
stabilized. On Day 26, the patient was discharged for a long convalescence. Clearing of
infiltration was observed via chest x-ray 6 weeks later. Recovery appeared to be complete
and no secondary cases developed.
This was the first reported case of primary pneumonic plague treated by sulfadiazine with
recovery. However, recovery cannot be attributed solely to administration of sulfadiazine.
As noted above, Dr. JH had received plague vaccine approximately 1 year prior to his
illness. It is unclear if this vaccine provided protection. The initiation of treatment within
26 hours of symptoms onset may have been a critical factor in successful recovery of this
patient.
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In addition to the summary above, Tieh, et al. reported on an outbreak of primary
pneumonic plague in 1946 (Tieh, 1948), where 5 of the 39 patients, not previously
vaccinated, were given sulfadiazine. Drug treatment was effective in 3 of the 5 patients,
and the 2 deaths were presumably due to not receiving treatment early enough.
2.3.2
Treatment with Sulfadiazine, Sulfamerzine, and Streptomycin
A bacteriologist, 33 years of age, working at the National Institutes of Health, Nanking,
China, became ill from an accidental laboratory infection with Y. pestis (Huang, 1948).
Due to the relevance of his work, the man had been vaccinated with 2 injections of
plague vaccine from Haffkine Institute in Nov 1942 and a single injection of a plague
vaccine prepared by the National Epidemic Prevention Bureau, China, in Dec 1943.
On the evening of 11 Feb 1947, the man began to have generalized malaise, aches and
fever, followed by headache and chills the next morning. Two days later (Day 3), he
developed a non-productive cough. At this time, his wife, a nurse, gave him 2 g of
sulfadiazine. A physician was consulted. The patient was observed to have respiratory
distress and dullness of the right lower lobe with diminished breath sounds but no rales.
Lobar pneumonia of the right lower lobe was suspected, and an additional 2 g of
sulfadiazine was administered that evening followed by 1 g every 4 hours.
Approximately 3 AM on 14 Feb (Day 4), he began to cough up thin, bloody sputum.
Y. pestis was suspected from microscopic examination of the sputum, which was
confirmed by culture and animal inoculation. The patient was moved to a temporary
isolation quarter where he stayed during the course of his illness.
Sulfadiazine was started approximately 48 hours and streptomycin, approximately
72 hours after onset of illness. The patient received a total of 97 g sulfadiazine between
13 Feb (Day 3) and 03 Mar (Day 21), when it was discontinued due to low white blood
cell count. Sulfamerzine was initiated, and a total of 104 g were given between 04 Mar
(Day 22) and 03 Apr (Day 52). Streptomycin intramuscular (IM) injections were started
on 14 Feb (Day 4) at 100,000 units every 3 hours. The dosage was increased to 2 to 3
million units per day when supplies of the drug improved. The patient received a total of
21,440,000 units between 14 Feb and 03 Mar. Gram-negative bacteria reappeared in his
sputum, and streptomycin was restarted on 17 Mar at 3 million units per day; a total of
18,150,000 units were administered over the next 7 days. Penicillin (1 million units) was
also given from 22 Feb through Mar 4 with the goal of preventing a secondary infection
with Gram-positive diplococci.
For the first 2 weeks of illness, the patient was critically ill - mentally clear but
occasionally drowsy and unreasonable. He complained of right-sided chest pain.
Respirations were labored with occasional cyanosis, and he continually produced bloody
sputum. On Day 8, chest examination revealed dullness and diminished breath in the
right lower lobe; rales were also present. Fever subsided on Mar 3 (Day 21), and within
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another week, coughing lessened and became less productive. Chest findings began to
improve slowly in early April.
To complicate matters, the patient contracted malaria from a blood transfusion given in
the first 2 weeks of illness; quinine was given and he promptly recovered. The patient
also developed jaundice for 10 days, starting 21 Apr. The condition resolved with a
proper diet and vitamin supplements. The patient was released from isolation on 07 May
(Day 86).
Sputum cultures were obtained throughout the course of illness. A pure culture of
Y. pestis was obtained on Day 4; this strain was sensitive to both streptomycin and
sulfadiazine. Slight synergy of the drugs in combination was observed. Bacilli isolated 26
Feb through 16 Mar were found to be avirulent in animal tests, and no Gram-negative
bacilli were found after 16 Mar. The organism isolated on 26 Feb was resistant to
streptomycin, with no inhibition of growth regardless of drug concentration, and sensitive
to sulfadiazine.
A total of 49 people who had lived on the same floor as the plague patient prior to his
isolation received sulfadiazine (3 g per day for 1 week). In addition, 15 close contacts
received sulfadiazine (6 g per day for 1 week) started after the confirmation of Y. pestis
infection. None of the contacts contracted the disease.
2.3.3
TreatmentwithTetracyclineandStreptomycin
In 1959, a laboratory-acquired case of pneumonic plague occurred at the US Army
Medical Unit, Walter Reed Army Medical Center, Fort Detrick, Maryland (Burmeister,
1962). A male chemist, 22 years of age, analyzed cultures of Y. pestis for nucleic acid
content was possibly exposed to the organism on 27 Aug 1959. Of relevance, he had been
vaccinated against plague in March of the same year with a booster on 10 Aug.
At 5 PM on 01 Sep (Day 1), this patient was admitted to the hospital complaining of
chills and fever for the past 9 hours, non-productive cough with pleuritic chest pain for
5 hours, and severe backache lower down with stiffness of the neck for 4 hours. On
admission, he appeared to be acutely ill holding his back and neck stiff. His deep, dry,
coarse cough was outwardly painful. Body temperature was measured at 103°F, pulse
was regular (96 bpm), and blood pressure, 100/60 mm Hg. The patient’s throat was
slightly reddened. A dullness over the left upper lung was observed, and breath sounds
were decreased over the entire left lung. Laboratory tests revealed a mild leukocytosis
with minimal left shift and an elevated C-reactive protein. Chest x-ray at admission
showed a small, ill-defined infiltrate in the left intraclavicular area.
Thirteen hours after the onset of symptoms (Day 2), the patient was given tetracycline
(3 g PO). At this time, body temperature had risen to 105.2°F, pulse to 110 bpm,
respiratory rate to 30 brpm, and blood pressure, 95/60 mm Hg. He remained alert and
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streaked sputum. Moist rales developed in the left intraclavicular area, and a friction rub
could be heard. Chest x-ray revealed increased patchy and linear infiltrate in the left
upper lobe. His leukocyte count had risen. Examination of his sputum confirmed
pneumonic plague, and the patient was isolated.
Shortly after midnight (Day 3 of symptoms), tetracycline (1 g IV) was administered due
to oral intolerance. At 3 AM, his temperature was 105°F, pulse was 120 bpm, and
respiratory rate was 40 brpm. He was flushed and hazy but remained alert and oriented.
Cough continued unassociated with pain, and minimal amounts of sputum were produced
at this time. Two hours after the start of IV tetracycline, streptomycin (1 g IM every
6 hours) was initiated, and the rate of tetracycline was increased to 1 g IV every 12 hours.
By mid-morning on Day 3, body temperature had decreased to 102°F respiratory rate to
28 brpm; however, the cough persisted. Later temperature was measured at 100.6°F, and
the patient was able to tolerate oral fluids.
The patient remained afebrile on Day 4; however, in the afternoon of the 5th day, body
temperature rose (102°F). Despite this, the patient appeared to improve overall.
Tetracycline (750 mg PO every 6 hours) was reinstituted. A sputum sample obtained that
evening revealed only an occasional intracellular plague bacillus. Temperature returned
to normal the following morning, and the patient remained afebrile thereafter.
Streptomycin was discontinued on Day 7; a total of 19 g had been received. A total of
30 g of tetracycline was administered over 10 days. He continued to improve and was
discharged 11 days after onset of symptoms, when his chest x-ray revealed complete
clearing. Y. pestis was isolated by culture and guinea pig inoculation from sputum
specimens obtained at admission and after 24 hours; no subsequent blood specimens were
positive.
Hospital personnel were given sulfadiazine (3 g per day) for 6 days. There were no
secondary cases.
2.3.4
Treatment with Chloramphenicol and Doxycycline
In 2004, a cluster of 4 cases of pneumonic plague occurred in Uganda - 2 concurrent
index patient/care-giver pairs (Begier, 2006). Of these, 3 patients received antibiotics.
One patient received chloramphenicol IV for 10 days and PO for 8 additional days; this
was the lone survivor.
The first index patient, a 22-year-old woman, had symptoms of headache, fever, and
chills for several days, followed by lymphadenopathy on Day 3. Cough was first noted on
Day 5 becoming productive with bloody sputum on Day 7. Chloroquine was initiated for
malaria on Day 6 for 3 days. Her productive and bloody cough increased in severity and
on Day 9, she died. This patient’s mother, a 40-year-old female, became ill 5 days after
her daughter’s death. On Day 1, she reported headache, fever, chills, weakness, chest
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pain, and a productive cough. Penicillin (IM, 6-times over 36 hours) was administered for
presumptive severe pneumonia. She died on Day 3 of her illness.
A second index patient, a male, 25 years of age, complained of headache, fever, and
chills. The man received anti-malaria treatment and penicillin (IM) for presumptive
severe pneumonia. On Day 5 of his illness, his cough was productive with bloody
sputum, and he died on Day 6. Five days after the man’s death, his sister and primary
caregiver, 30 years of age, developed dyspnea and elevated temperature 39.3°C (102.7°F)
with respiratory rate at 56 brpm. Assistance was required to walk. Examination of her
chest revealed bilateral coarse crepitations. Twenty-nine hours after onset of illness,
chloramphenicol (2 g IV bolus) and doxycycline (100 mg PO) were administered. Upon
admission to the hospital, chloramphenicol (1 g IV) was administered 1.75 hours after the
initial dose (the staff was unaware of the previous dose). Chloramphenicol (1 g IV every
6 hours) was continued for 48 hours, then at a reduced dose (750 mg every 6 hours) for a
total of 10 days of IV treatment. She was discharged on Day 10 and given
chloramphenicol (750 mg PO every 6 hours) for an additional 8 days. Three weeks later
she had fully recovered.
Frontal chest radiographs taken on Days 2, 3, and 18 of illness revealed bilateral airspace
disease predominantly in the lower lobes and bilateral pleural effusions without evidence
of hilar or mediastinal lymphadenopathy. These findings were consistent with multilobar
pneumonia that improved over that time.
Y. pestis was identified from the patient’s sputum by polymerase chain reaction and a
direct fluorescent-antibody microscopy using Y. pestis-specific antibody. Bacterial
cultures of her sputum, collected shortly after treatment administration and suboptimally
stored and transported, did not yield Y. pestis.
All identified close contacts of the caregivers received cotrimoxazole (960 mg PO twice
per day) for 3 days.
2.3.5
Summary of Treated Clinical Course of Pneumonic Plague
The initial symptoms of untreated pneumonic plague are as described in Section 2.2.
Provided that Y. pestis infection can be confirmed in the first 24-48 hours and antibiotics
started immediately thereafter, symptoms should be alleviated over the next 7-10 days,
which is dependent upon the severity of infection, the timing of treatment post infection,
and the antibiotic used. Clearing of infiltration via chest x-ray should be observed over
the next few weeks.
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2.4 The African Green Monkey Model of Pneumonic Plague Comparison of Human and Animal (African Green Monkey)
Natural Courses of Pneumonic Plague
DMID/NIAID sponsored a series of studies that established the AGM model for
pneumonic plague as a well-characterized animal model for predicting response in human
pneumonic plaque. A comparison of the characteristics of human disease using the
literature data presented above and the data obtained in the nonclinical studies with
regard to clinical signs and symptoms, pathophysiology, disease progression, radiology,
and histopathology are presented in this section. A fair comparison of natural cases of
pneumonic plague in humans to experimental infections of AGMs requires recognition of
the limitations of comparisons and differences between these diseases. The human cases
summarized are based on the diagnosis of pneumonic plague rather than route of
exposure. While the route of exposure and timing can be surmised from some of the
human case reports, it is not always known. For human cases of inhaled Y. pestis, the
dose is unknown, while the dose in AGMs was measured. The inhaled dose (CFU) of Y.
pestis varies from animal to animal based on respiratory minute volume; however, it is
likely to be equal to or greater than the level of exposure in the human cases summarized
above. The timing of signs and symptoms in human cases are sometimes described
relative to the first sign or symptom and sometimes relative to the time of presumptive
exposure; whereas, timing in the animal studies is always relative to exposure. Clinical
symptomatology, such as headache, chills, and myalgia, are not obtainable in animal
studies, and therefore, no comparison can be made. While descriptions of the course of
human disease demonstrated variability in presentation or care-seeking behavior, the
animal studies are conducted in controlled, laboratory settings and there is less apparent
variability as presentation is not a variable.
In Wu Lien-Teh’s 1926 treatise (Wu Lien-Teh, 1926) the time course of human disease
was reported to be 2 to 9 days, with the majority of cases being 2 to 5 or 6 days. All other
case studies presented here fit within the overall time frame of 2 to 9 days. This time
course matches exactly that seen in the AGM studies summarized here and in Davis et al.
(1996) (i.e., 2 to 9 days).
Fever is a clinical sign noted consistently in both humans and AGMs. Among the human
cases summarized in this document, only a few descriptions made no mention of fever:
Dr. Manser’s nurse, and two of the three refugees whose descriptions only refer to
suspicion of plague or the lack of plague-like symptoms. All other cases noted a fever.
This is consistent with the AGM model, in which all animals present with a fever,
typically at 72 hours post-exposure. The most compelling human case description that
determined the interval between exposure and fever is the wildlife biologist exposed
during necropsy of a mountain lion, where the time to fever was 3 days (Wong, 2009).
This coincides with the time to fever seen in the AGM studies.
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Most human cases presented here were confirmed as pneumonic plague based on the
presence of Y. pestis bacilli found in sputum rather than blood. The AGM model
correlated fever with the presence of bacteria in the blood; however, observations in these
studies of sputum or frothy discharge from nares, with or without blood, are consistent
with the progression of cough in human disease. Both of the Battelle natural history
studies cultured fluid from the lung and nasal discharge for the presence of Y. pestis. In
all 20 animals, Y. pestis was found at death in both nasal discharge and lung fluids.
Heart rate and respiratory rate were noted in the clinical summaries to be elevated during
the course of disease, particularly in the cases followed by Chun and Wu Lien-The (Chun
[a,b], 1936; Wu Lien-Teh, 1926). These observations were typically made daily, while in
the AGM studies, they were monitored continuously via telemetry, except for respiratory
rate in study F03-09G, which was measured visually, though frequently. The increased
respiratory rate tends to be more dramatic in late disease in both human and AGM cases.
Heart rate is also increased in both humans and AGMs.
In humans, changes in pulmonary function were mainly gathered through auscultation.
Although auscultation was not performed in the AGM, the character of respiration was
assessed during scheduled and frequent observations. Rales were observed in both
humans and AGMs; 3 of 4 diseased animals in F03-09G had rales observed just prior to
euthanasia/death. Chest radiographs were performed in 2 AGM studies (F03-09G and
FY06-126) and were summarized in NIAID’s Independent Review of Radiology
(NIAID-Yp-NatHis-Rad-2011). Pulmonary infiltrates in AGMs were mild to moderate on
Day 3 and severe at the time of death. This is consistent with the clinical radiological
findings reported by Alsofrom et al. (Alsofrom, 1985), where 8 of 9 cases were reported
as bilateral pulmonary infiltrates, compared to approximately 65% in AGMs.
There are few published reports of human pathology (Doll, 1994; Werner, 1984; Wong,
2009) and macroscopic and microscopic pathology findings are very similar in human
and AGM cases of pneumonic plague. Pathology findings reported in humans were: lobar
to sublobar pulmonary consolidation (3 of 3), inflammatory infiltrates (neutrophils with
fibrin) (2 of 3), hemorrhagic and frothy fluid in both lungs (1 of 3), pulmonary exudates
and effusions (1 of 3), bronchopneumonia (1 of 3), and the presence of bacilli (2 of 3).
Note that these findings are taken directly from a small number of published reports and
were not independently determined. The most prominent pulmonary findings in the
independent review (Appendix A) of 36 untreated AGMs were bacteria, edema,
hemorrhage, inflammatory infiltrate (intra-alveolar neutrophils followed by
macrophages), and pleural fibrin. These pathology findings in the AGM are essentially
indistinguishable from those reported in human cases.
Table 1 summarizes a comparison of the main features of pneumonic plague between
humans and AGMs. In summary, the clinical presentations are strikingly similar, with no
differences observed that would indicate that the AGM model is a less-than-satisfactory
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model of human pneumonic plague. Therefore, the AGM model is a reasonably wellcharacterized model for the testing of antibiotics that may have utility as treatment
options in humans following known or suspected exposure to Y. pestis; this satisfies the
requirements under the Code of Federal Regulations (CFR), Animal Rule (21 CFR
314.610).
Table 1 Human and African Green Monkey Natural Courses of Pneumonic Plague
Humana
African Green Monkeyb
Time course of disease, days
2 to 9
2 to 9
Elevated in ~100% of cases
Elevated in 100% of cases
Temperature
(at 3 days in 1 case)
(typically 3 days post-exposure)
Positive in 100% of blood and/or
Yersinia pestis present
Positive in 100% of sputum
lung/nasal fluids
Heart rate
Elevated
Elevatedc
Respiration rate
Elevated late in disease
Elevated late in disease
Pulmonary infiltrates
Pulmonary infiltrates
Chest radiographs
90% bilateral
Approximately 65% bilateralc
Consolidations,
Bacteria,
Inflammatory infiltrates,
Edema,
Hemorrhagic/frothy fluid,
Hemorrhage,
Pathology, lung
Exudates and effusions,
Inflammatory
Bronchopneumonia,
infiltrates/bronchopneumonia,
Bacilli
Pleural fibrin
a
Data from 3 cases in 3 publications (Doll, 1994; Werner, 1984; Wong, 2009)
b
Data from 34 untreated AGMs from 4 studies (F03-09G, FY06-126, 617-G607610, and 875-G607610)
and Davis, 1996
c
Heart rate and radiograph data from F03-09G and FY06-126
Clinical signs/tests that could potentially serve as a trigger for treatment were bacteremia,
body temperature, heart rate, and respiratory rate; chest radiographs were also considered
though are not possible at all study sites. Body temperature, heart rate, respiratory rate
and chest radiographs can be real-time triggers, but bacteremia requires up to 48 hours of
culture. It is also worth noting that bacteremia and chest radiographs are limited in
frequency due to animal welfare concerns about blood volume and anesthesia, while
body temperature, heart rate and respiratory rate, were monitored continuously by
telemetry. In practice, chest radiographs were obtained upon the appearance of other
signs such as increased respirations or body temperature. Body temperature, heart rate,
respiratory rate and chest radiographs are all general signs and only bacteremia is specific
to Yersinia pestis infection. Therefore, it was important to determine the correlation of
bacteremia with other clinical signs. Comparing body temperature, heart rate and
respiratory rate as possible treatment triggers, body temperature increased significantly
and maximally early, while increases in heart and respiratory rates began at the same time
and continued to increase as disease severity progressed, with maximal levels appearing
late in disease. Two challenged survivors never exhibited increased body temperature,
heart or respiratory rates and were also never bacteremic. Initial chest radiographs, at the
time of first clinical signs (fever) were abnormal (predominately mild) and increased in
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severity until death (moderate to marked/severe). Therefore, fever was selected as the
treatment trigger for the study of ciprofloxacin efficacy.
3
Summary of Ciprofloxacin Pharmacokinetics in the African Green
Monkey Model and Translation to Human Dosing
In support of the initial marketing approval of Cipro® NDA 19-537, the pharmacokinetic
profile of ciprofloxacin was characterized in humans and in nonclinical studies.
This section summarizes the ciprofloxacin absorption, distribution, metabolism and
excretion (ADME) information for African Green monkeys derived from USAMRIID
Study B126-03 that supports the ciprofloxacin efficacy study described in Section 4 as
well as from the efficacy study (USAMRIID Study A05-04G). This pharmacokinetic
(PK) study (B126-03) used saline as the vehicle. Information on these studies is provided
in Table 2.
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Table 2 Ciprofloxacin ADME Nonclinical Studies Conducted to Support the Plague Indication
Study Type
(Study No.)
Absorption
Single and
f
Repeat-Dose PK
(B126-03)
Species/Strain/N
Route of Administration/
(Vehicle/Test Formulation)
Duration of Dosing
Dose
a
(mg/kg)
GLP Status
Monkey/African Green
b
(3/sex)
c
Phase I: PO (nasogastric)
once (SDE)
c
152025
GLP
d
Phase II: IV (20-min inf.)
once
e
Phase III: IV (20-min inf.)
d
e
14 days
d
15
e
20
(2.5, 3.33 and 4.17 mg/mL ciprofloxacin in
0.9% NaCl)
Efficacy Study
(A05-04G)
a
b
c
d
e
f
g
h
g
Monkey/African Green
(6/sex)
IV infusion 60 min q 12 h
q 12 h x 10 days
h
15
GLP
Unless otherwise noted.
The same monkeys were used at each dose and/or phase of dosing.
Phase I: Monkeys (3/sex) administered PO single escalating doses of ciprofloxacin on Day 1, Day 15, and Day 29; doses were separated by a 2-week washout period.
Phase II: Monkeys received a single dose of ciprofloxacin via IV infusion (20-minutes) on Day 43.
Phase III: Monkeys received a daily IV infusion (20-minutes) of ciprofloxacin for 14 days (Day 71 to Day 84).
Study conducted at SRI International, 333 Ravenswood Ave, Menlo Park, CA, USA.
Study conducted at U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD, USA.
10/12 Monkeys received 15 mg/kg q 12 hours IV infusion (60-minutes) of ciprofloxacin for 10 days. 2/12 were nontreated controls.
ADME = Absorption, distribution, metabolism, and excretion; AGM = African Green monkeys; GLP = Good Laboratory Practice; No. = number; IV = intravenous;
N = number of animals or samples; NA = not applicable; NaCl = sodium chloride; PK = pharmacokinetic; q 12 h = every 12 hours; PO = orally; SDE = single dose escalation.
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3.1 Methods of Analysis
During the current program, two bioanalytical assays, one in serum and one in plasma were
developed in order to support the assessment of ciprofloxacin concentrations in the blood of
African Green monkeys. Both are based on a high performance liquid chromatography assay
with fluorescence detection (HPLC/FLD) separation/detection technology. A summary of the
bioanalytical methods and a description of the analyses used in each particular study, as well as
information on the performance of the assays are provided below.
3.1.1
Bioanalytical Methodology for PK Study B126-03
Plasma samples from Study B126-03 were analyzed using a HPLC/FLD method. This was
developed by SRI International for the detection and quantitation of ciprofloxacin in African
Green monkey plasma samples obtained from the PK study (B126-03). An internal standard
(levofloxacin) was added to plasma samples, followed by precipitation of the monkey plasma
proteins with acetonitrile and subsequent centrifugation. The resulting supernatants were
evaporated under vacuum, and the residues reconstituted in the mobile phase used in the HPLC
system. HPLC analysis of the reconstituted samples used isocratic elution of a reverse phase
column maintained at 40°C with a mobile phase that was 85% by volume 10 mM L isoleucine
and 5 mM copper(II) sulfate in water and 15% methanol. Detection of ciprofloxacin and the
internal standard was by fluorescence detection (λex=335nm, λem=475nm), which gave the
method sufficient specificity and sensitivity to permit measurement of as little as 0.10 µg/mL
ciprofloxacin when 100 µL of monkey plasma was analyzed.
Calibration ranges for ciprofloxacin were 0.10 to 10.0 µg/mL. Tests to assess specificity,
linearity, accuracy and precision of the assay were within acceptable levels of specification.
Freeze/thaw stability analysis of quality control (QC) samples frozen at ≤-70 °C and then thawed
at room temperature revealed no significant decrease in analyte concentration after three cycles.
Plasma samples that were thawed and stored at room temperature for 1 hour and then analyzed in
triplicate exhibited a loss of ciprofloxacin upon analysis. Study samples were processed
immediately upon thawing and were not permitted to remain at room temperature prior to
extraction.
3.1.2
Bioanalytical Methods Supporting Efficacy Study A05-04G
An HPLC/FLD assay was developed at the U.S. Army Medical Research Institute of Infectious
Diseases (USAMRIID) for the determination of ciprofloxacin in African Green monkey serum.
This method (VP-013), was used in support of the efficacy study (A05-04G).
In this assay, serum proteins were precipitated by the addition of 70% perchloric acid to a 100
µL aliquot of African Green monkey serum. The sample was vortexed and centrifuged. Twenty
µL of the supernatant was diluted into 980 µL of mobile phase buffer (25 mM potassium
dihydrogen phosphate, 0.01% triethylamine). A 100 µL injection was made into the HPLC.
This was eluted isocratically with an 83:17 ratio of mobile phase buffer and acetonitrile. The
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HPLC/FLD analysis was conducted by monitoring fluorescence at an excitation wavelength of
280 nm and an emission wavelength of 446 nm.
Calibration ranges for ciprofloxacin were 0.10 to 10.0 µg/mL. The results of the stability study
conducted to support the method validation indicated that ciprofloxacin was stable in serum
stored at -70°C for 14 months. Freeze/thaw stability had been demonstrated for 3 cycles in
report B126-03 and was not repeated. Post-preparative stability of extracted serum samples was
proven for 3 days at room temperature and when stored at 4ºC.
3.2 Absorption
Ciprofloxacin was administered to AGMs as a single oral dose of 15, 20, or 25 mg/kg, a single
20-min intravenous (IV) infusion of 15 mg/kg, or a 14-day repeated IV infusion of 20 mg/kg/day
(B126-03). Ciprofloxacin was absorbed after oral (PO) administration to AGMs; however, the
maximum plasma concentration (Cmax) and area under the concentration vs. time curve (AUC)
values did not increase in a dose-proportional manner following oral dosing. Following IV
infusions of 15 and 20 mg/kg, peak plasma concentrations were proportional to dose. Repeated
IV infusions of 20 mg/kg did not alter the AUC0-inf or the elimination half-life, but did result in
an increased average Cmax (11.70 to 27.33 µg/mL). The mean IV plasma half-life of
ciprofloxacin in AGMs ranged between 2.36 and 3.37 hours. It was slightly longer following
oral dosing, ranging between a mean of 2.69 and 4.78 hours. Bioavailability (F%) averaged
43%, 26% and 44% at doses of 15, 20 and 25 mg/kg, respectively. In general, different doses
have little effect on the elimination half-life (t1/2) of ciprofloxacin in the AGM.
Information on the study design and results of these studies is provided in Table 3 and discussed
in Section 3.2.1 and Section 3.3.1.
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Table 3 Mean Pharmacokinetic Parameters Following Single or Repeat Does of Ciprofloxacin in African
Green Monkeys
Study Type/
(Study No.)
N
Single and
3/sex
a
Repeat-Dose PK
(B126-03)
Duration
PO
once
(SDE)
15
once
(SDE)
20
0.49 1.83
b
(0.15) (0.40)
8856
(2505)
4.27 4.78 1260
(1.21) (0.91) (228)
26
once
(SDE)
25
1.69 1.50
(1.59) (0.77)
8370
(3684)
9.01 4.46 1276
(4.84) (1.44) (228)
44
15
9.34 0.31
(0.89) (0.06)
6118
(991)
12.12 3.37 1277
(2.43) (0.57) (235)
NA
IV
14 days
(20-min inf.) (1st dose)d
20
11.70 0.30
(1.56) (0.07)
5456
(802)
18.83 2.80 1361
(3.22) (0.33) (236)
NA
IV
14 days
(20-min inf.) (last dose)
20
27.33 0.23
(23.95) (0.08)
4815
(779)
17.82 2.36 1447
(3.22) (0.50) (291)
NA
PO
PO
IV
(20-min inf.)
Efficacy Study
(05-04G)
a
b
c
d
e
e
6/sex
Vz or
CL or
tmax
Vz/F AUC(0-) t1/2
CL/F
F
(h) (mL/kg) (µg·h/mL) (h) (mL/h/kg) (%)
Route
Dose
Cmax
(mg/kg) (µg/mL)
c
once
IV
q 12 h for
60- min inf. 10 days
15
1.66
1.01
5376
4.83
2.69 1401
43
Day 2
3.49
b
(0.55)
Day 6
3.91
(0.58)
Day 10
4.03
(1.22)
Study B126-03 consisted of 3 phases; monkeys (3/sex) were re-used at each dose and study phase. In Phase I, monkeys
received single escalating PO (nasogastric) doses of 15, 20, and 25 mg/kg on Day 1, Day 15 and Day 29, respectively,
with a 2-week washout period between doses. In Phase II, monkeys received a single 20-minute IV infusion of 15
mg/kg on Day 43, and in Phase III, monkeys received daily 20-minute IV infusions of 20 mg/kg for 14 days, from Day
71 to Day 84.
Values in parentheses are standard deviation.
At this lowest dose, 3/6 animals had sufficient data for calculation of pharmacokinetic parameters. The values in the
table represent the mean values for only those 3 animals and thus overestimate the exposure of the group.
PK values are shown for Phase III of Study B126-03 for the first (Day 71) and last (Day 84) of 14 days of IV doses.
12 AGMs exposed to inhalational plague. 10/12 were treated with ciprofloxacin and 2 were nontreated controls.
AGMs were sampled 5 minutes after infusion completion Day 2, Day 6 and Day 10. Trough concentrations in all
animals were <0.5 µg/mL.
AGM = African Green monkeys; h = hours; inf. = infusion; IV= intravenous; min = minutes; N = number; NA = not
applicable; NC = not calculable from existing data; PO = oral; SDE = single dose escalation
3.2.1
Absorption After Single Escalating PO Doses Administered in a Multi-Phase Study in
African Green Monkeys (Study B126-03)
The pharmacokinetic profile of ciprofloxacin was examined following single (PO and IV) and
repeated (IV) dosing in AGMs (B126-03). The study was conducted in three phases, and used
2.5, 3.33 and 4.17 mg/mL solutions of ciprofloxacin formulated in 0.9% sodium chloride (NaCl).
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In Phase I of the study, monkeys received sequential PO (nasogastric) doses of ciprofloxacin at
doses of 15, 20, and 25 mg/kg on Day 1, Day 15, and Day 29, respectively, with a 2 week
washout period between doses. After a subsequent 2-week washout period, the same monkeys
received a single 20-minute IV infusion of 15 mg/kg on Day 43 (Phase II), and in Phase III, all
monkeys were given a 20 minute IV infusion of 20 mg/kg ciprofloxacin once daily for 14 days
(Day 71 to Day 84). Blood samples were collected for pharmacokinetic assessment for each of
the three study phases. Samples for Phase I were collected on Day 1, Day 15, and Day 29 at the
following timepoints (predose, 0.5, 1, 2, 5, 8, 12 and 24 hours postdose). Blood samples for
Phases II and III were collected on Day 43, Day 71, and Day 84, respectively, before dosing and
at 5, 10, 20, 35, 50, 80, 140, 320, 500 and 740 minutes after the start of the IV infusion. Plasma
was harvested, and samples analyzed for the presence of ciprofloxacin by means of high
performance liquid chromatography with fluorescence detection HPLC (HPLC/FLD).
A summary of findings obtained after single PO administration is discussed below, while results
obtained following single and repeated IV administration (Phases II and III) are discussed in
Section 4.3.1 and are presented in Table 3.
Ciprofloxacin was absorbed in a non-dose-proportional manner after PO administration of single
escalating doses of 15, 20, and 25 mg/kg, with mean time to maximum plasma concentration
(tmax) values of 2.69 and 4.78 hours. Neither Cmax nor AUC increased in a dose proportional
manner after PO administration (average Cmax 1.66, 0.49 and 1.69 µg/mL and AUC0-∞ values
4.83, 4.27 and 9.01 µg•h/mL), respectively, after PO doses of 15, 20 and 25 mg/kg. It should be
noted that at the 15 mg/kg PO dose only 3/6 animals had a sufficient number of detectable
plasma samples to allow calculation of pharmacokinetic parameters. The presented values are a
mean of only these three animals and therefore over-estimate the exposure of the 15 mg/kg PO
dose group.
The large average volumes of distribution seen after PO administration (5376 to 8856 mL/kg)
indicate extensive distribution to extravascular sites, as may the mean elimination half-lives (t1/2:
2.69 to 4.78 hours) observed. Average plasma clearance (CL/F) rates were rapid (1260 to 1401
mL/h/kg) and independent of dose level. The PO bioavailability of ciprofloxacin was variable at
the doses examined (i.e., 43%, 26% and 44% at 15, 20, and 25 mg/kg, respectively). No major
differences in the disposition of ciprofloxacin in male and female monkeys were observed after
single PO administration.
3.3 Pharmacokinetic Parameters, Bioequivalence and/or Bioavailability
3.3.1
Single and/or Repeated Dosing in African Green Monkeys (Study B126-03 and A05-04G)
The plasma kinetics of ciprofloxacin in healthy AGMs following IV infusion was investigated in
study B126-03. Three monkeys per sex were given ciprofloxacin as part of a multi-phase study
in order to compare the effects of single (PO and 20 min IV infusion) versus repeated (20-min IV
infusion for 14 days) dosing.
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A comparison of kinetics after PO or IV dosing indicated that ciprofloxacin was eliminated from
the plasma with a slightly longer half-life after single PO dosing than after single or repeated IV
infusion (t1/2: 2.69 to 4.78 hours PO versus 2.36 to 3.37 hours IV, respectively). Additionally, it
is likely that the large t1/2-values and volume of distribution (Vz) values noted after both single
PO (Vz: 5376 to 8856 mL/kg) or single and repeated IV infusion (Vz: 4815 to 6118 mL/kg) may
be due to the extensive distribution of ciprofloxacin to extravascular sites. Mean plasma
clearance rates of ciprofloxacin were rapid and comparable for both PO and IV routes of
administration following either administration of a single dose (CL/F: 1260 to 1401 mL•h/kg); or
administration of 14 days of repeated IV infusion (1447 mL•h/kg). No significant gender related
differences in pharmacokinetic parameters were observed after the administration of
ciprofloxacin via single PO or IV infusion, or after repeated IV infusion for 14 days.
Peak and trough plasma concentrations were evaluated in the efficacy study (A05-04G). Twelve
AGMs were exposed to inhalational plague. Ten of the 12 were drug treated and 2 were
nontreated controls. In drug-treated animals, ciprofloxacin was administered as a 15 mg/kg IV
infusion over 60 minutes on a q 12 hours schedule. Animals were sampled for serum
ciprofloxacin concentrations immediately prior to the start of drug infusion and 5 minutes after
the completion of drug infusion on Day 2, Day 6 and Day 10 of treatment. Blood volume
limitations precluded taking sufficient samples for full pharmacokinetic profiles.
All trough concentrations (Day 2, Day 6 and Day 10) were <0.5 µg/mL. Mean peak serum
ciprofloxacin concentrations were 3.49 ± 0.55 µg/mL, 3.91 ± 0.58 µg/mL and 4.03 ± 1.22 µg/mL
on Day 2, Day 6 and Day 10 of treatment, respectively.
Additional information is presented in Table 3.
3.4 Toxicological Findings in PK Study B126-03
While the primary purpose of a single (PO and IV) and repeated (IV) multi-phase study in
African Green monkeys (B126-03) was to assess pharmacokinetic parameters, potential toxicity
was also assessed. Results following toxicologic assessment indicated that ciprofloxacin was
well tolerated, with no ciprofloxacin-related changes in food consumption, body weight, serum
chemistry, hematology, coagulation or urinalysis parameters noted.
3.5 Distribution
The binding of ciprofloxacin to serum proteins is reported to be in the range of 20% to 40% in
humans (Cipro® label). This is not considered high enough to cause protein binding interactions
with other drugs.
Plasma protein binding, tissue distribution and placental transfer have not been investigated in
the AGM.
3.6 Metabolism
Ciprofloxacin is reported to not be subjected to first pass metabolism in humans.
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No metabolism studies have been conducted in the AGM.
3.7 Excretion
In humans, a substantial fraction (40% to 50%) of ciprofloxacin is excreted in urine as
unchanged drug. Urinary excretion of ciprofloxacin is virtually complete within 24 hours of
dosing. A smaller fraction of the ciprofloxacin dose is excreted in bile as unchanged drug or as
metabolites. The duration of this excretion is longer and may occur over 5 days.
Studies on the excretion of ciprofloxacin in the AGM were not conducted.
3.8 Pharmacokinetic Drug Interactions
No additional in vitro or in vivo nonclinical pharmacokinetic drug interaction studies have been
conducted in support of this PIND.
3.9 Dose Selection - Ciprofloxacin Exposure in humans and the AGM Efficacy
Model
In humans, an IV infusion of 400 mg over 60 minutes results in an average Cmax of 4.56 µg/mL
and an AUC0-12 of 12.7 µg•h/mL. The goal of the pharmacokinetic studies described in these
sections was to determine whether mimicking this exposure in AGMs could be successful in
treating inhalation plague post-exposure. The FDA selected the dose, schedule, and infusion
duration for the efficacy study based on PK modeling simulations conducted there.
In the AGM efficacy study, peak plasma levels following IV infusion of 15 mg/kg given over 60
minutes averaged 3.49 µg/mL (Day 2), or 77% of the human exposure at 400 mg. Due to blood
volume limitations, the efficacy study lacked sufficient PK sampling to determine the AUC.
Trough plasma concentrations were below 0.5 µg/mL. The lower than human exposure of
ciprofloxacin in the AGM suggests the efficacious treatment of pneumonic plague with
ciprofloxacin in the AGM animal model is relevant to the treatment for humans.
3.10 Pharmacokinetic Summary
In support of the initial marketing approval of Cipro® NDA 19-537, the pharmacokinetic profile
of ciprofloxacin was characterized in humans and in nonclinical studies.
The proposed indication of ciprofloxacin in the post-exposure treatment of pneumonic plague
(Yersinia pestis) is supported by a pivotal efficacy study in the African Green monkey (A0405G), and thus the objective of the presented ADME information is to bridge PK information
from the previously existing database with PK studies in African Green monkeys (B126-03).
Exploratory studies attempted to identify exposure levels in African Green monkeys comparable
to or below those seen in humans at the clinical dose of 400 mg IV (Cmax and AUC values of
4.56 µg/mL and 12.7 µg•h/mL, respectively). The dosing regimen used in the efficacy study, 15
mg/kg q 12 hours via 60-minute IV infusion, was selected to mimic concentrations achieved in
the clinical dosing regimen.
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Pharmacokinetic data in African Green monkeys was consistent with that previously known
about ciprofloxacin, and no major differences in the disposition of ciprofloxacin in male and
female monkeys were observed after PO or IV administration. Ciprofloxacin was absorbed after
PO administration, however, non-dose-proportional changes in mean Cmax and AUC0-∞ values
were observed after single PO doses. Repeated IV administration for 14 days resulted in
increased Cmax values without substantial changes in AUC or elimination t1/2 values on Day 1
and Day 14 of dosing. Target human plasma levels (4.56 µg/mL) were exceeded in the
PK/toxicology study (a dose of 15 mg/kg given over 20 minutes resulted in an average Cmax of
9.34 µg/mL). Therefore, the FDA recommended a prolonged infusion duration (60 minutes q 12
hours) for ciprofloxacin administration in the efficacy study in AGMs. Clearance rates were
rapid and comparable for both routes of administration (1260 to 1447 mL•h/kg). The large Vz
values seen after PO and IV dosing indicate extensive distribution to extravascular sites. The PO
bioavailability of ciprofloxacin ranged between 26% to 44%, making it less than that reported in
humans (approximately 70%). The efficacy study in AGMs was conducted using only IV
dosing.
4
Summary of Ciprofloxacin Efficacy
In this section of the briefing document, the efficacy of ciprofloxacin in the treatment of
pneumonic plague will be established. In vitro microbiology and in vivo rodent studies were
conducted with ciprofloxacin and showed the activity of ciprofloxacin against Y. pestis. Results
of pharmacokinetic studies in AGMs were used to develop simulations matching human
exposure for doses of 400 mg (intravenous) or 500 mg (oral). Based on these results, an IV
dosing regimen of 15 mg/kg twice daily at an infusion ratio of 0.125 mL/min/kg over 60 minutes
for 10 days was selected for use in the pivotal efficacy study conducted in the AGM model.
Results from this study demonstrate that ciprofloxacin is effective in the treatment of pneumonic
plague in the AGM at doses relevant to human exposure.
4.1 In Vitro
4.1.1
Ciprofloxacin Susceptibility Testing in Y. pestis
The U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) conducted a
study that determined the activity of ciprofloxacin against 30 genetically diverse isolates of Y.
pestis. Ciprofloxacin MICs were determined by the broth microdilution method according to
methods established by the Clinical and Laboratory Standards Institute (CLSI) (CLSI, 2008).
Endpoints were determined both at 24 hours and 48 hours of incubation following addition of the
test article but only the value at 48 hours is reported. The ciprofloxacin MIC50, MIC90 and range
were 0.015 µg/mL, 0.015 µg/mL, and 0.008-0.03 µg/mL, respectively, which were similar to
those observed for other fluoroquinolones (Table 4). The MIC for the CO92 strain used in the
pivotal AGM study was 0.015 µg/mL.
The Health Protection Agency (HPA), (Porton Down, UK) conducted a study that determined
the activity of ciprofloxacin and gentamicin against 12 isolates of Y. pestis including 11 clinical
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outbreak strains from the National Collection of Type Cultures (NCTC) as originally sourced
from various countries. Ciprofloxacin MICs ranged from ≤0.015 to 0.12 µg/mL with an MIC50
value of 0.015 µg/mL and an MIC90 value of 0.06 µg/mL (Table 4). Importantly, the MIC for the
CO92 strain used in the pivotal AGM study was 0.03 µg/mL. Gentamicin MICs ranged from
0.25 to 4 µg/mL. All isolates were ciprofloxacin- and gentamicin-susceptible using current CLSI
breakpoints (CLSI, 2008).
Published data pertaining to the in vitro susceptibility of Y. pestis to ciprofloxacin, substantiates
the MIC data presented in Table 4. In a study of 78 Y. pestis isolates from Vietnam collected
from 1985 to 1993, ciprofloxacin had agar dilution MIC90s of 0.062 µg/mL (Smith, 1995).
Another study of 94 isolates collected by the French army from 1964-1988 reported agar dilution
MIC90s of <0.125 µg/mL for ciprofloxacin (Hernandez, 2003).
A study by Ryzhko et al. (Ryzhko, 2009) reported low MICs for ciprofloxacin (0.01 to 0.02
µg/mL) for 40 Y. pestis isolates which included 20 encapsulated and 20 non-encapsulated strains.
In a study of 28 isolates from Namibia collected during the period of 1982 to 1991, ciprofloxacin
was reported to have an MIC90 value of 0.031 µg/mL (Frean, 2003). In the study by Lonsway
(Lonsway, 2011), ciprofloxacin MIC90 value and range were 0.12 µg/mL and ≤0.03 to 0.5
µg/mL, respectively, for 26 Y. pestis isolates from the CDC and USAMRIID. Lastly, the range
of MICs for 8 strains tested by broth dilution were reported by Russell and coauthors as <0.063
to 0.125 µg/mL (Russell, 1998).
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Table 4 In Vitro Susceptibility of Y. pestis to Ciprofloxacin
Country or
Laboratory
USAMRIID
HPA
Anti-Plague
Scientific
Research Institute
Russia
USAMRIID and
CDC
Vietnam
a
Method
N
MIC50
Broth dilution 30 0.03
Broth dilution 12
0.03
Agar dilution
NR
40
Broth dilution 26
Etest
Agar dilution 78
NR
NR
0.031
French Army
Collection
Namibia
Agar dilution
94
<0.12
Agar dilution
28
0.016
UK
Broth dilution
8
NA
MIC (µg/mL)
Range
MIC
a
Year
(Reference)
90
0.03
0.008-0.12
NR
(RIID-YpCMIC2010)
0.06 ≤0.015-0.06
NR
(HPA-YpCMIC2008)
NR
0.01-0.02
NR
(Ryzhko, 2009)
0.12
0.06
0.062
≤0.03-0.5
0.008-0.12
0.008-0.062
NR
(Lonsway, 2011)
1985-1993
(Smith, 1995)
<0.12 <0.12-0.12
1964-1988
(Hernandez, 2003)
0.031 0.016-0.031
1982-1991
(Frean, 2003)
NA
<0.06-0.12
NR
(Russell, 1998)
Year in which isolates were identified.
CDC = United States Centers for Disease Control and Prevention; HPA = Health Protection
Agency; MIC = minimal inhibitory concentration; MIC50 = minimal inhibitory concentration at
which 50% of isolates are inhibited; MIC90 = minimal inhibitory concentration at which 90% of
isolates are inhibited; NA = not applicable; NR = not reported; UK = United Kingdom;
USAMRIID = United States Army Medical Research Institute of Infectious Diseases.
4.1.2
In Vitro Hollow-Fiber Infection Model
Louie and coauthors used the in vitro pharmacodynamic, hollow-fiber infection model to
simulate treatment of Y. pestis infections with ciprofloxacin (Louie, 2011). In the model,
untreated bacteria grew from 107 to 1010 colony forming units (CFU/mL) over 10 days. In this
study, conditions that simulated the human serum concentration-time profiles of ciprofloxacin
500 mg PO q12 h were able to reduce the bacterial densities from 108 CFU/mL to undetectable
(<102 CFU/mL) and did not detectably select for resistant mutants. The human serum
concentration-time profile used in this hollow fiber model was mimicked in the African Green
monkey efficacy study (A05-04G).
4.2 In Vivo
4.2.1
Efficacy of Ciprofloxacin in African Green Monkeys with Pneumonic Plague
A single study was performed with the objective of testing the efficacy of ciprofloxacin for
treatment of pneumonic plague in AGMs. This study was performed in compliance with Good
Laboratory Practice (U.S.) requirements, with the exception of the water and feed analysis, the
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ciprofloxacin HPLC assay which was not validated at the time of the study, and other minor
items noted in the study report compliance statement.
Experimental Design
A total of 12 research naïve, healthy animals were placed on study, 10 animals were assigned to
the treatment group who received ciprofloxacin (Group A) and 2 animals to the placebo-treated
group who received 5% dextrose (Group B). Animals were approximately 3 to 6 kg and adults
(>2 years old) when placed on study. Prior to study initiation, telemeters to monitor body
temperature and activity were implanted subcutaneously, and dual-lumen venous catheters were
inserted. Baseline telemetry data was collected for 7 days prior to aerosol challenge with Y.
pestis. On the day of exposure, prior to challenge, animals were anesthetized and body weights
were obtained in addition to plethysmography. Blood specimens were obtained from all animals
for baseline CBC (complete blood counts), bacteriology, clinical chemistry and ciprofloxacin
levels.
4.2.1.1 ChallengeMaterialandDose
The Y. pestis CO92 challenge material was freshly prepared using the same procedures as those
used for the natural history studies conducted in establishment of the AGM model for pneumonic
plague. The challenge material was prepared by inoculating Tryptose blood agar base (TBAB)
slants with Y. pestis strain CO92 and incubating for two days at 26 to 30°C. On the day of
challenge, the slant cultures were suspended in Heart Infusion Broth (HIB), pooled, vortexed and
the concentration was determined by optical density reading at 620 nm. The material was diluted
in HIB to the target concentration of 3x106 CFU/mL and subsequently verified to be 3.3x106
CFU/mL. Aerosol challenges were carried out on two different days, and animals in each group
were challenged on each day according to the design in Table 5.
Table 5 A05-04G Efficacy Study Design
Placebo (Group B)
a
Treatment (Group A )
a
Cohort 1
(15 April 2005)
1
5
Cohort 2
(29 April 2005)
1
5
Total
2
10
Group A = ciprofloxacin treated
Animals were anesthetized on Day 0, and each animal was exposed to the Y. pestis aerosol in a
head-only chamber in a Class III biosafety cabinet, with a target dose of 100 + 50 LD50
equivalents. Minute volume was measured by whole-body plethysmography just prior to
challenge, determining the time of exposure required to meet the target challenge dose. Each
animal’s actual challenge dose was verified retrospectively by collecting the aerosol during the
challenge in an all glass impinger and quantifying organisms by plating dilutions.
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engeClinicallAssessmen
nts
4.2.1.2 Post‐Challe
After chaallenge, cliniical observattions were reecorded twicce daily alonng with contiinuous telem
metry
monitorin
ng. Blood sp
pecimens weere obtained
d every otherr day startingg on Day 3 ffor bacterem
mia,
assessed quantitativeely by serial dilution and
d plating on ttryptic soy aagar, and CBC analysis. In
addition, blood speciimens were collected
c
on Day 3, Dayy 7 and Day 115 for clinical chemistryy
analysis and
a on Day 5, Day 9, an
nd Day 13 fo
or ciprofloxaacin level meeasurements.. A complette
necropsy
y was conduccted on all an
nimals that died
d or weree euthanized..
4.2.1.3 TreatmentTrigger
Placebo and
a ciproflox
xacin infusio
ons began when
w
the maj ority of anim
mals in each challenge cohort
exhibited
d the treatmeent trigger off a fever of tw
wo hours duuration, or att 76 hours poost-challengee,
whicheveer time pointt occurred so
ooner. The trreatment triggger of feverr was defined as a body
temperatu
ure greater than
t
1.5°C over baselinee for two houurs.
4.2.1.4 CiprofloxaccinDoseSele
ection
The 15 mg/kg
m
dose of
o ciprofloxaacin was chosen to mimi c human phaarmacokinettics, based onn
simulatio
ons using thee pharmacok
kinetic data obtained
o
in S
Study B126--03 and show
wn in Figure 2.
A detaileed discussion
n of the dosee selection iss found in Seection 3.9.
Figure 2 Simulated
S
Steeady-State Cip
profloxacin Co
oncentrations in African Grreen Monkeyss and Observeed
Values in Humans Follo
owing Intraveenous Infusion
n
AGM = African
n Green monkey;; mcg = microgrram; ml = millilitter; SD = standaard deviation
4.2.1.5 CiprofloxaccinTreatment
Placebo and
a ciproflox
xacin infusio
ons occurred
d twice dailyy for 60 minuutes. The treeatment grouup,
Group A, received ciiprofloxacin at 15 mg/kg
g body weighht every 12 hhours for 10 days, for a ttotal
of 20 infu
fusions. Placcebo-treated animals (Grroup B) receeived similarr volumes off 5% dextrose.
Blood waas drawn forr peak and trrough drug leevels immeddiately prior to and withiin 5 minutess of
completion of the inffusion on Daay 2, Day 6 and
a Day 10; Challenge C
Cohort 1 sam
mples were
drawn in the afternoo
on and Challlenge Cohortt 2 samples w
were drawn in the mornning to
accommo
odate availab
bility of stafff.
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4.2.1.6 Results
The average challenge dose for each of the challenge days was 109 ± 16 LD50 equivalents, and
110 ± 8 LD50 equivalents, respectively. Individual challenge doses are presented in Table 6. All
of the challenge doses were well within the target range and the standard deviation for the study
was very good, less than 11% (110 ± 12 LD50 equivalents). All animals developed fevers
between 70 and 76 hours post-challenge. The first Challenge Cohort was treated as a group at 72
hours post-challenge, as the majority of animals exhibited the treatment trigger of a fever of two
hours in duration, while Challenge Cohort 2 was treated as a group at 76 hours post-challenge.
All animals were bacteremic at the time of treatment initiation.
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3.00x10
W352
B
2
F
110
9.93x10
A
1
F
124
2.83x10
A
1
M
92
7.17x10
A
1
F
97
1.90x10
A
1
F
97
5.40x10
A
1
M
127
1.43x10
A
2
M
118
5.73x10
A
2
M
112
2.43x10
A
2
F
96
2.90x10
A
2
M
114
2.20x10
A
2
F
110
1.93x10
V494
V463
V527
W319
V246
V515
V286
W318
V524
W161
a
b
c
d
Last Bacteremia,
CFU/mLd
119
Time to Death, hours
M
Outcomec
Challenge Dose, LD50
equivalents
1
Initiation of Treatment, h
Sexb
B
Bacteremia at time of
treatment, CFU/mL
Challenge Cohort
V311
Animal ID
Groupa
Table 6 A05-04G, Ciprofloxacin Efficacy, Challenge Dose, Survival, Treatment Initiation and Bacteremia
Observations
1
72
EU
99
5
2.30x10
5
76
D
98.5
>1.0x10
3
72
S
–
– 3
72
S
– – 2
72
S
– – 3
72
S
– – 3
72
D
248.5
NG
3
76
S
– – 3
76
S
– – 3
76
S
– – 4
76
S
– – 3
76
S
– – 8
A = ciprofloxacin treated; B = control
F = female; M = male
D = Found dead; EU = Euthanized; S = survived to Day 28
– = not applicable (animal survived to Day 28); NG = no growth
Both placebo-treated animals (Group B) became bacteremic and demonstrated a fever on Day 3
and died on Day 4. Both of the control animals had terminal bacteremia at levels consistent with
those reported in the natural history studies. Nine of ten treated animals completed the 10 day
course of treatment with ciprofloxacin and survived; the animal that did not survive (V246)
experienced a complete catheter failure on Day 7 post-challenge (after 4 days of treatment; 8
infusions total) and treatment was discontinued. Based on ciprofloxacin levels measured in this
animal, it is clear that the catheter was compromised from at least Day 2 of the treatment period.
The animal’s fever returned on Day 8 post-challenge and the animal died on Day 11 post 46 of 109
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challenge. This animal was not bacteremic after 2 and 4 days of treatment (4 and 8 infusions,
respectively) and then positive after 6 days of treatment, which was the next blood sample after
catheter failure. While the terminal blood sample was not positive for Yersinia pestis, the
pathology report noted that bacilli were present in the lungs. Fever in all other treated animals
generally resolved after 2 to 4 days of treatment with ciprofloxacin. Mortality due to pneumonic
plague for animals that received ciprofloxacin (1/10) was statistically significantly lower than the
placebo-treated group (2/2 [p=0.0455]) using a one-tailed Fisher’s Exact Test.
All animals were bacteremic prior to treatment, and treated animals generally exhibited no
further Y. pestis once treatment with ciprofloxacin began, becoming negative by the next daily
blood draw. Four of ten treated animals had a subsequent-to-treatment positive bacteremia,
though all at reduced levels (1.5 to 3 log reduction). Three animals (V494, W319 and V524)
were mildly bacteremic on the second day of treatment (<150 CFU, following a 1 to3 log
reduction) and negative thereafter, surviving until the scheduled study termination on Day 28.
A complete gross necropsy was performed on the three animals that died or were euthanized:
one placebo-treated animal died, one placebo-treated animal was euthanized, and one treated
animal (V246) died after catheter failure and cessation of treatment. All gross necropsy
observations were recorded and whole blood was collected, if possible, for quantitative
bacteriology. The following tissues were collected at necropsy fixed in 10% neutral buffered
formalin for microscopic evaluation: axillary lymph node, inguinal lymph node, brachial plexus,
mandibular salivary gland, mandibular lymph node, spleen, left and right kidney, right and/or left
adrenal glands, liver, gallbladder, fundic stomach, duodenum, pancreas, mesenteric lymph node,
jejunum, ileum, cecum, proximal and distal colon, testis or ovary, uterus or prostate gland,
urinary bladder, tongue, tonsil, larynx, thyroid gland, trachea, esophagus, mediastinum, lungs,
trachea-bronchial lymph nodes, heart, diaphragm, sciatic nerve with adjacent skeletal muscle,
femoral bone marrow, nares, upper lip, left and right eyes, cerebrum, cerebellum, pituitary gland
and identification chip. A summary of the most common pathology findings, by group, appears
in Table 7. Findings in the placebo-treated group are very similar to the findings observed in the
natural history studies.
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Table 7 A05-04G: Incidence of Prominent Pathology Findings in Ciprofloxacin Treated and Placebo Groups
Group A
Group B
Treated
Controls
1
2
Lung, alveolar fibrin
1
0
Lung, bacteria
1
2
Lung, edema
1
2
Lung, hemorrhage
1
2
Lung, granulomatous inflammation
1
0
Lung, inflammatory infiltrate intra-alveolar,
macrophage
1
2
Lung, inflammatory infiltrate intra-alveolar,
neutrophil
1
1
Lung, pleura, fibrin
1
2
Mediastinal lymph node, bacteria
0
2
Mediastinal lymph node, hemorrhage
0
2
Mediastinal lymph node, inflammatory
infiltrate, neutrophil
1
2
Spleen, bacteria
0
1
Spleen, congestion
0
1
Spleen, inflammatory infiltrate, neutrophil
0
1
Spleen, plasmacytosis
1
0
Number examined
4.2.1.7 Conclusion
In summary, the efficacy of ciprofloxacin in treating pneumonic plague in AGMs was evaluated.
Under the conditions of this study, ciprofloxacin administered intravenously for ten days at 15
mg/kg every 12 hours resulted in a 90% survival rate (9 of 10 animals) compared to a 0%
survival rate in untreated control animals (a statistically significant difference, p=0.0001 by
Fisher’s Exact Test including historical controls). The one ciprofloxacin-treated animal that died
did not receive the proposed dose of ciprofloxacin due to a failure of the administration catheter.
Circulating ciprofloxacin concentrations were below 0.5 µg/mL at all timepoints tested in this
animal. In the other antibiotic-treated animals, the dosing regimen of ciprofloxacin used in the
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AGM mimicked the human pharmacokinetic profile. Fever in the treated survivors typically
resolved after two to four days of ciprofloxacin treatment while bacteremia generally resolved
before the next daily blood draw.
5
Safety Profile of Ciprofloxacin
Oral ciprofloxacin was approved by the FDA for the treatment of bacterial infections in 1987. In
1991, an intravenous formulation was approved. The drug has been available in generic form
since 2004. It is available as 250, 500, and 750 mg tablets, 250 and 500 mg/5 mL suspensions
and as an IV dosing solution (200 mg/100 mL, 400 mg/200 mL and as 10 mg/mL).
Ciprofloxacin is a fluoroquinolone antibiotic that has been approved for treatment of numerous
urinary tract, respiratory, skin, and soft tissue infections. Ciprofloxacin is widely used and its
safety profile has been well established at dosage regimens in adults of 250 to 750 mg given
twice daily for up to 14 days.
Ciprofloxacin was approved by FDA in November 2000 for the treatment of inhalational anthrax
(post-exposure). The recommended dosage regimen in adults is 500 mg given twice a day for 60
days. Pediatric patients receive 10 mg/kg (maximum of 400 mg/dose) IV or 15 mg/kg
(maximum of 500 mg/dose) for 60 days. The approved dosage regimen for inhalational anthrax
is substantially longer than the proposed dose regimen for pneumonic plague.
Given the severity of disease and the shorter treatment period for pneumonic plague, as
compared to anthrax, safety issues are not expected. The established safety profile of
ciprofloxacin covers a wider range of dose strengths and treatment duration than the
recommended dose regimen for the treatment of pneumonic plague.
As with the anthrax indication, clinical trials of ciprofloxacin for treatment of plague infection as
might occur in the event of a biologic attack are neither ethical nor feasible. Consequently, the
efficacy data for the treatment of pneumonic plague are based on a non-human primate study
conducted in AGMs (Study A05-04G).
This animal efficacy study was conducted using a dose and schedule resulting in serum
concentrations that align with those seen in humans when the drug is used in accordance with a
currently approved dose and schedule (400 mg IV q 12 hours). Therefore, it is expected that
previous findings of clinical safety for ciprofloxacin will be applicable to this indication. The
dosing recommendation for the treatment of pneumonic plague is the same as the currently
approved dosing, and for shorter duration than the recommended adult and pediatric doses for
inhalational anthrax (post-exposure).
The most frequently reported drug related adverse events, from clinical trials of all formulations,
all dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were
nausea, diarrhea, abnormal liver function tests, vomiting, and rash.
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Other reactions, occurring less frequently are detailed in the ciprofloxacin label and are only
summarized here. Reported adverse events include: headache, abdominal pain/discomfort,
injection site reactions, cardiovascular reactions including palpitation, central nervous system
(CNS) reactions such as dizziness and insomnia, gastrointestinal reactions, lymphatic reactions,
changes in amylase and lipase levels, musculoskeletal events (foot pain, pain, pain in
extremities). Renal reactions (polyuria, renal failure, urinary retention) respiratory reactions
(dyspnea, epistaxis) and skin reactions have all been reported. Further safety information
including information on warnings and precautions is provided in Appendix B.
Ciprofloxacin is specifically contraindicated in patients with a history of hypersensitivity to
ciprofloxacin or any other member of the quinolone class and in cases of co-administration with
tizanidine.
There are few important drug-drug interactions with ciprofloxacin. Protein binding is in the
range of 20%-40%, making it unlikely that protein binding interactions with other drugs would
occur. Ciprofloxacin inhibits P-450 1A2 (CYP1A2) which would lead to the elevation of levels
of methylxanthines specifically theophylline and caffeine. Co-administration with ciprofloxacin
increases the effects of warfarin and inhibits the renal excretion of methotrexate which increases
the toxicity associated with that agent.
Rare but serious adverse events were originally detected in the FDA’s Adverse Event Reporting
System (AERS) database. In 1996, the FDA published an alert about a correlation between
ciprofloxacin use and acute tendon rupture. A ‘black box’ warning was later added to the
product label and package insert. The warning presently states: “Fluoroquinolones, including
[ciprofloxacin], are associated with an increased risk of tendonitis and tendon rupture at all ages.
This risk is further increased in patients older than 60 years of age, in patients taking
corticosteroid drugs, and in patients with kidney, heart or lung transplants.” The risk of acute
tendon rupture associated with ciprofloxacin use is estimated to be 6 to 37 ruptures per 100,000
people (Suchak, 2005). This risk is four times greater than age matched controls. If a person
was using corticosteroids, the relative risk increases to 46 fold (Suchak, 2005).
In 2011, another ‘black box’ warning was added concerning the use of fluoroquinolones in
patients with myasthenia gravis. The warning presently states: “Fluoroquinolones, including
[ciprofloxacin], may exacerbate muscle weakness in persons with myasthenia gravis. Avoid
[ciprofloxacin] in patients with known myasthenia gravis.” Ciprofloxacin, like all of the
fluoroquinolones, have neuromuscular blocking activity. That activity can become clinically
relevant in individuals with myasthenia gravis.
In preclinical testing, ciprofloxacin was demonstrated to cause lameness in immature dogs. The
histopathologic cause of this lameness was permanent lesions in the cartilage. For all age ranges,
the label describes clinical studies that demonstrate an increase incidence of adverse events
related to joints and surrounding tissues with ciprofloxacin compared to other antimicrobial
agents. Despite this preclinical finding, ciprofloxacin has a pediatric indication for complicated
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urinary tract infection/pyelonephritis. This indication was added to the label in 2004. While not
a first choice antibiotic in this population, ciprofloxacin is indicated for this condition.
Ciprofloxacin is also indicated for the treatment of pediatric inhalation anthrax.
The use of ciprofloxacin in several special populations requires attention. For pediatrics there is
suggested milligram per kilogram dosage. In lactating women, there is no toxicity signal. In
pregnant women, there are animal studies that have shown adverse effects on the fetus. Multiple
human studies have not demonstrated any risk. In the geriatric population, there is an increased
risk of acute tendon rupture. In individuals with renal failure the dose has to be modified if the
person has a creatinine clearance less that 50 mL/min.
The risks and benefits associated with the use of ciprofloxacin are well documented.
Pneumonic plague is a disease has the potential to be used as a bioweapon. The prognosis of
patients with untreated pneumonic plague is very poor. The fatality rate of this disease, if
untreated, could be as high as 90 to 100% (Bogen, 1925).
The proposed treatment for pneumonic plague based on the efficacy of ciprofloxacin in the AGM
model uses ciprofloxacin at lower doses and for a shorter duration than for other severe diseases.
Ciprofloxacin has been deemed safe and effective at higher doses and for longer durations in the
treatment of severe respiratory infections and complicated bone and joint infections. The
survival benefit of post-exposure treatment with ciprofloxacin at previously approved dosing
regimens clearly outweighs the risk of known adverse events associated with the use of
ciprofloxacin.
6
Summary
In 2001-2002, a United States Food and Drug Administration/National Institutes of Health
(FDA/NIH) Antibiotic Working Group met and discussed the development of therapeutic
options for pneumonic plague and inhalation anthrax. During these discussions, the FDA and
NIH selected ciprofloxacin as one of the antibiotic candidates for a potential treatment indication
for pneumonic plague. The Division of Microbiology and Infectious Diseases (DMID), National
Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH)
undertook a program to investigate and establish the African Green monkey (AGM) as a model
in pneumonic plague and to study the use of antibiotics, including ciprofloxacin, for the
treatment of pneumonic plague.
In vitro microbiology and in vivo rodent studies were conducted with ciprofloxacin and showed
the activity of ciprofloxacin against Y. pestis. Results of pharmacokinetic studies in AGMs were
used to develop simulations matching human exposure for doses of 400 mg (intravenous) or 500
mg (oral). Based on these results, an IV dosing regimen of 15 mg/kg twice daily at an infusion
ratio of 0.125 mL/min/kg over 60 minutes for 10 days was selected for use in the pivotal efficacy
study conducted in the AGM model. Results from this study demonstrate that ciprofloxacin is
effective in the treatment of pneumonic plague in the AGM at doses relevant to human exposure.
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In conclusion, the data presented in this briefing document support the use of ciprofloxacin in the
treatment of the pneumonic plague.
7
References
Alsofrom DJ, Mettler FA, Mann JM. Radiologic manifestations of plague in New Mexico, 19751980: A review of 42 proved cases. Radiology 1985;139:561-5.
Begier EM, Asiki G, Anywaine Z, Yockey B, Schriefer ME, Aleti P, et al. Pneumonic plague
cluster, Uganda, 2004. Emerg Infect Dis 2006;12(3):460-7.
Bogen E. The pneumonic plague in Los Angeles. Cal West Med 1925;23:175-6.
Burmeister RW, Tigeritt WD, Overholt EL. Laboratory-acquired pneumonic plague: report of a
case and review of previous cases. Ann Int Med 1962;56(5):789-800.
Chun JWH [a]. Clinical features. In Wu Lien-Teh, Chun JWH, Pollitzer R, and Wu CY. Plague:
A manual for medical and public health workers. Shanghai Station, China: Weishengshu
National Quarantine Service; 1936:309-33.
Chun JWH [b]. Therapy and personal prophylaxis. In Wu Lien-Teh, Chun JWH, Pollitzer R, and
Wu CY. Plague: A manual for medical and public health workers. Shanghai Station, China:
Weishengshu National Quarantine Service; 1936:334-53.
Cipro® Drug Label
CLSI. Performance standards for antimicrobial susceptibility testing: 18th informational
supplement. M100-S18. 2008. Clinical and Laboratory Standards Institute.
Davis KJ, Fritz SL, Pitt ML, Welkos SL, Worsham PL, et al. Pathology of experimental
pneumonic plague produced by fraction 1-positive and fraction 1-negative Yersinia pestis in
African green monkeys (Cercopithecus aethiops). Arch Pathol Lab Med. 1996; 120:156-163.
Dennis DT, Mead PS. Yersinia species, including plague. In Mandell, Douglas, and Bennett’s
Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill Livingstone;
2009:2943-53.
Doll JM, Zeitz PS, Ettestad P, Bucholtz AL, Davis T, Gage K. Cat-transmitted fatal pneumonic
plague in a person who traveled from Colorado to Arizona. Am J Trop Med Hyg
1994;51(1):109-14.
Frean J, Klugman KP, Arntzen L, Bukofzer S. Susceptibility of Yersinia pestis to novel and
conventional antimicrobial agents. J. Antimicrob. Chemother. 2003; 52: 294-6.
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Hernandez EM, Girardet M, Ramisse F, Vidal D, Cavallo J_D. Antibiotic susceptibilities of 94
isolates of Yersinia pestis to 24 antimicrobial agents. J. Antimicrob. Chemother. 2003; 52:
1029-31.
Huang CH, Huang CY, Chu LW. Pneumonic plague: A report of recovery in a proved case and
a note on sulfadiazine prophylaxis. Am J Trop Med Hyg 1948;28(3):361-71.
Inglesby TV, Dennis DT, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, et al. Plague as a
biological weapon: medical and public health management. J Am Med Assoc.
2000;283(17):2281-90.
Link VB. A history of plague in the United States of America. [Public Health Monograph No.
26]. Washington DC: US Government Printing Office 1955.
Lonsway DR., Urich SK, Heine HS, McAllister SK, Banerjee SN, Schriefer ME, Patel JB.
Comparison of etest method with reference broth microdilution method for antimicrobial
susceptibility testing of Yersinia pestis. J. Clin. Microbiol. 2011; 49: 1956-60.
Louie AB, VanScoy B, Liu W, Kulawy R, Brown D, Heine HS, et al. Comparative efficacies of
candidate antibiotics against Yersinia pestis in an in vitro pharmacodynamic model. Antimicrob.
Agents Chemother. 2011: AAC.01374-10.
Louisiana Office of Public Health - Infectious Disease Epidemiology Section - Infectious
Disease Control Manual. Plague. [Revised 09/25/2004] Available at:
http://www.dhh.state.la.us/offices/miscdocs/docs-249/Manual/PlagueManual.pdf. Accessed 08
July 2011.
Munter EJ. Pneumonic plague: Report of a case with recovery. J Am Med Assoc.
1945;128:281-3.
Russell PS, Eley M, Green M, Stagg AJ, Taylor RR, Nelson M, et al. Efficacy of doxycycline
and ciprofloxacin against experimental Yersinia pestis infection. J. Antimicrob. Chemother.
1998; 41: 301-5.
Ryzhko IV, Tsuraeva RI, Anisimov BI, Trishina AV. Efficacy of levofloxacin, lomefloxacin and
moxifloxacin vs. Other fluoroquinolones in experimental plague due to F1+ and F1- strains of
Yersinia pestis in albino mice. Antibiot. Khimioter. 2009; 54: 37-40
Suchak AA, Bostick G, Reid D, Blitz S, Jomha N. The incidence of Achilles tendon ruptures in
Edmonton, Canada. Foot Ankle Int. 2005;26(11):932-6.
Simpson WJ. A treatise on plague: dealing with the historical, epidemiological, clinical,
therapeutic, and preventive aspects of the disease. Cambridge, England: University Press; 1905.
Available at: http://www.books.google.com. Accessed 19 Sep 2011.
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Smith, MD, Vinh, DX, Hoa TT, Wain J, Thung D, White NJ. In vitro antimicrobial
susceptibilities of strains of Yersinia pestis. Antimicrob. Agents Chemother. 1995; 39: 2153-4.
Tieh TH, Landauer E, Miyagawa F, Kobayashi G, Okayasu G. Primary pneumonic plague in
Mukden, 1946, and report of 39 cases with 3 recoveries. J Infect Dis 1948;82(1):52-8.
Werner SB, Weidmer CE, Nelson BC, Nygaard GS, Goethals RM, Poland JD. Primary plague
pneumonia contracted from a domestic cat at South Lake Tahoe, Calif. J Am Med Assoc.
1984;251(7):929-31.
Wong D, Wild MA, Walburger MA, Higgins CL, Callahan M, Czarnecki LA, et al. Primary
pneumonic plague contracted from a mountain lion carcass. Clin Infect Dis 2009;49:e33-38.
Wu Lien-Teh. A Treatise on Pneumonic Plague. Geneva, Switzerland: League of Nations. III.
Health Organization; 1926:241-95.
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Appendix A
Independent Pathology Review Summary
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Independent Pathology Review
An independent review of microscopic slides from animals in United State Army Medical Research
Institute of Infectious Diseases (USAMRIID) study number A05-04G entitled, ‘Ciprofloxacin Therapy
for Pneumonic Plague in the African Green Monkey (Chlorocebus aethiops)’ was conducted in an effort
to apply terminology consistent with that used in the evaluation of tissues in the Natural History studies
conducted with Yersinia pestis Strain CO92.
The general approach to recording microscopic changes resulting from this review of the pathology
assessments from these studies was consistent with the perspective and methods provided by Crissman et
al 2004, Haschek et al 2010, Shackelford et al 2002, and Wolf and Mann 2005.
It is important to note that the tissue list for microscopic evaluation in USAMRIID A05-04G is different
from that evaluated in the Natural History studies conducted at BBRC and LRRI. The only tissues
evaluated microscopically in all animals from all natural history studies were lungs and
bronchial/tracheobronchial lymph nodes. USAMRIID A05-04G evaluated mediastinal lymph nodes but
not bronchial/tracheobronchial lymph nodes. In addition, the number and/or location of routine sections
of lung processed to slide for microscopic evaluation were different for each study (LRRI Natural History
study FY06-126 - 7 sections; BBRC study 617- 2 sections; BBRC study 875- 4 sections; USAMRIID
F03-09G and USAMRIID A05-04G - 4 sections but not the same locations as in BBRC 875). Each study
handled the processing of pulmonary gross lesions in different ways. LRRI for example, always obtained
and processed a section of ‘lesioned’ lung tissue. In Battelle study 617, gross lesions in the lung were, in
general, processed to slide and evaluated which resulted in the evaluation of from 2 to 7 sections of lungs
from animals in this study. Because pneumonic plague in the African Green Monkey appears to be lobar
to sublobar in nature, the number and selection of lung tissue presented for microscopic evaluation can
result in variability in both character and severity of microscopic findings. For this reason, the
independent reviewer used overall descriptive findings for lung for the study specific Independent
Pathology Review Table which combines all the findings from the various sections presented for
evaluation.
The independent review of microscopic slides from the control animals from USAMRIID A05-04G
confirms the common pathology associated with inhaled Y. pestis Strain CO92 in African Green Monkeys
as described in the Natural History studies. Both control animals were found dead or sacrificed in a
moribund condition on Day 4 post-challenge. Intra-alveolar inflammatory infiltrates (neutrophil and or
macrophage) were present in lungs of both control animals. There were remarkable lobar and/or sublobar
differences in the presence, severity and/or character of the infiltrates. In a single animal in the natural
history studies, for example, there might be intra-alveolar and intracellular (alveolar macrophages)
bacteria, minimal to moderate edema (serous and fibrinous exudates), and a mild to moderate
inflammatory infiltrate of primarily macrophages (very few neutrophils) in the left caudal lung lobe
whereas the right caudal lung lobe might have large numbers of bacteria widespread in the alveolar
spaces, moderate to marked neutrophilic inflammatory infiltration, mild edema, mild to moderate
hemorrhage, and fibrinous pleuritis (necrotizing pneumonia). Those areas where edema, macrophages
and bacteria predominate appear to represent earlier lesions in the disease process. As the disease
progresses unchecked, large numbers of neutrophils flood into the affected areas along with hemorrhage
and edema which eventually totally efface the normal lung tissue elements. Bacteria are seen in large
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numbers in the lung and are typically observed in both the alveolar spaces as well as within alveolar
macrophages.
All ciprofloxacin-treated animals survived to Day 28 post-challenge with the exception of animal A246
which did not receive the 10 days of treatment due to a catheter failure. Treated animals that survived to
study termination (Day 28 post-challenge) were not euthanized so there was no macroscopic or
microscopic evaluation of tissues from ciprofloxacin-treated animals with the exception of animal A246.
Animal A246 did not receive ciprofloxacin treatment according to the treatment schedule due to a
catheter failure and was found dead on Day 11 post-challenge. This animal had macroscopic and
microscopic changes similar to those observed in control (untreated animals) with the addition of
granulomatous inflammation and intra-alveolar fibrin which are thought to represent early attempts at
lesion resolution.
A summary of the microscopic findings in the lung is found in Table 1.
Table 1 Summary of Microscopic Findings in the Lungs
Tissue/Observation
Number Examined
Lung
Alveolus, fibrin
Bacteria
Edema
Hemorrhage
Inflammation, granulomatous
Inflammatory infiltrate, intra-alveolar, macrophage
Inflammatory infiltrate, intra-alveolar, neutrophil
Pleura, fibrin
Within normal limits
USAMRIID
A05-04G
Control Treated
Animals Animalsa
2
1
0
2
2
2
0
2
1
2
0
1
1
1
1
1
1
1
1
0
USAMRIID = United States Army Medical Research Institute of Infectious Diseases
a
Ciprofloxacin treated
Of the lymphoid tissues/organs evaluated, several were affected in the control animals of USAMRIID
A05-04G. Microscopic evaluation of the mediastinal lymph nodes and spleen from the control animals in
USAMRIID A05-04G revealed similar findings to those observed in the Natural History studies. The
findings in the mediastinal lymph nodes included, bacterial colonization, edema, hemorrhage, and
inflammatory infiltrates (primarily neutrophil). One or more of the following changes were observed in
the spleen the control animals evaluated in USAMRIID A05-04G: Bacteria, congestion, and
inflammatory infiltrates (neutrophil).
Microscopic evaluation of mediastinal lymph nodes and spleen from the treated animal that died after
treatment catheter failure revealed changes which were moderate in severity and included a neutrophilic
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inflammatory infiltrate in the lymph node and plasmacytosis in the spleen. Bacteria were not observed in
the sections of these tissues submitted for microscopic evaluation.
A summary of the microscopic findings in the mediastinal lymph nodes and spleen is found in Table 2.
Table 2 Summary of Microscopic Findings in the Mediastinal Lymph Nodes and Spleen
Tissue/Observation
Number Examined
Lymph Node, Mediastinal
Bacteria
Edema
Hemorrhage
Inflammatory infiltrate, neutrophil
Within normal limits
Number Examined
Spleen
Bacteria
Congestion
Inflammatory infiltrate, neutrophil
Plasmacytosis
Within normal limits
USAMRIID A05-04G
Control
Treated
Animals Animalsa
2
1
2
1
2
2
0
0
0
0
1
0
2
1
1
1
1
0
0
0
0
0
1
0
USAMRIID = United States Army Medical Research Institute of Infectious Diseases
a
Ciprofloxacin treated
In conclusion, an independent pathology review was conducted of the microscopic slides from animals in
United States Army Medical Research Institute of Infectious Diseases (USAMRIID) study number A0504G entitled, ‘Ciprofloxacin Therapy for Pneumonic Plague in the African Green Monkey (Chlorocebus
aethiops).’
Microscopic evaluation of the tissues provided from the control animals confirmed the common
pathology associated with lethal infection by inhaled Y. pestis Strain CO92 in African Green Monkeys as
described in the Natural History studies. Morphologic changes in the lung appear to begin as lobar to
sublobar serous and fibrinous exudates (edema) with intra-alveolar and intracellular (macrophages)
bacteria along with increased numbers of alveolar macrophages. These changes observed in the lung
transition quickly to diffuse necrotizing pneumonia characterized by alveoli and airways filled with
bacteria, inflammation and hemorrhage. There is also dissemination of bacteria to lymph nodes and
spleen which initiate changes in the tissues such as hemorrhage, inflammation and edema.
Under the conditions of this study, nine of the ten ciprofloxacin-treated animals survived to study
termination on Day 28 post challenge. The one treated animal that died prior to study termination had a
treatment catheter failure before the protocol-specified treatment plan was completed. This animal had
similar microscopic findings to the untreated control animals with the addition of pulmonary
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granulomatous inflammation and alveolar fibrin which are thought to represent early attempts at lesion
resolution.
The extensive Interlaboratory Microscopic Finding Incidence Table are found on the following pages of
this Appendix.
References:
Crissman JW, Goodman DG, Hildebrandt PK, Maronpot RR, Prater DA, Riley JH, Seaman WJ, Thake
DC. (2004). Best practices guideline: toxicologic histopathology. Toxicol Pathol. 32:126-31.
Haschek WA, Rousseaux CG and Wallig MA. (2010). Nomenclature: terminology for morphologic
alterations. In: Fundamentals of toxicologic pathology, Second Edition, pp 67-80. Academic Press, San
Diego.
Shackelford C, Long G, Wolf J, Okerberg C, Herbert R. Qualitative and quantitative analysis of
nonneoplastic lesions in toxicology studies. Toxicol Pathol. 2002 Jan-Feb;30(1):93-6.
Wolf DC and Mann PC. (2005). Confounders in interpreting pathology for safety and risk assessment.
Toxicol Appl Pharmacol. 202:302-8.
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Interlaboratory Microscopic Finding Incidence Summary
Natural History Studies of Pneumonic Plague following Aerosol Challenge
and USAMRIID A05-04G (Ciprofloxacin Efficacy Study)
African Green Monkeys; Male and Female
Incidence of Neoplastic and Non-Neoplastic Microscopic Findings
Natural History Study
USAMRIID A05-04G
LRRI
USAMRIID
BBRC BBRC
FY06F03-09G
617
875
126
Tissue/Observation
b
c
10
10
10
No. of Animals:
4
Adrenal glands
No.
Examined:
Congestion
Corticomedullary junction,
amyloid
Sinusoids, bacteria
Within normal limits
Artery/Aorta
No.
Examined:
Within normal limits
Bone marrow
No.
Examined:
Bacteria
Myeloid hyperplasia
Within normal limits
Brachial plexus
No.
Examined:
Within normal limits
Brain
No.
Examined:
Meninges, bacteria
Within normal limits
Epididymis
No.
Examined:
Within normal limits
Controls
Treated
2
10
0
0
0
4
2
1
–
–
–
0
2
1
–
–
–
1
0
0
–
–
–
–
–
–
0
3
1
0
0
0
0
0
0
4
2
1
–
–
–
4
2
1
0
0
0
4
2
1
–
–
–
–
–
–
–
–
–
2
2
0
1
0
1
0
1
0
0
0
0
4
2
1
–
–
–
4
2
1
10
1
10
4
2
1
0
10
1
0
0
10
0
4
0
2
0
1
0
0
0
2
1
1
–
–
–
2
1
1
a
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Incidence of Neoplastic and Non-Neoplastic Microscopic Findings
Natural History Study
USAMRIID A05-04G
LRRI
BBRC BBRC
USAMRIID
FY06617
875
F03-09G
Tissue/Observation
126
b
c
10
10
10
No. of Animals:
4
Esophagus
No.
0
0
0
4
Examined:
Adventitia, hemorrhage
–
–
–
1
Bacteria
–
–
–
1
Inflammatory infiltrate,
–
–
–
1
neutrophil
Within normal limits
–
–
–
3
Eye
No.
Examined:
Within normal limits
Gallbladder
No.
Examined:
Autolysis precludes evaluation
Within normal limits
Heart
No.
Examined:
Myocardium, fibrosis
Myocardium, interstitium,
cellular infiltrate,
lymphoplasmacytic
Protozoal cyst
Within normal limits
Ileocecal junction
No.
Examined:
Submucosa, cellular infiltrate,
lymphoplasmacytic
Within normal limits
Intestine, large, colon No.
Examined:
Tunica muscularis, hemorrhage
Inflammatory infiltrate,
neutrophil
Within normal limits
Controls
Treated
2
10
2
1
0
0
0
0
0
0
2
1
0
0
0
4
2
1
–
–
–
4
2
1
0
0
0
4
2
1
–
–
–
–
–
–
3
1
2
0
1
0
10
0
0
4
2
1
1
–
–
1
0
0
0
–
–
1
0
0
1
8
–
–
–
–
0
2
0
2
0
1
0
0
0
4
0
0
–
–
–
1
–
–
–
–
–
3
–
–
0
0
0
4
2
1
–
–
–
1
0
0
–
–
–
1
0
0
–
–
–
3
2
1
a
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Incidence of Neoplastic and Non-Neoplastic Microscopic Findings
Natural History Study
USAMRIID A05-04G
LRRI
BBRC BBRC
USAMRIID
FY06617
875
F03-09G
Tissue/Observation
126
b
c
10
10
10
No. of Animals:
4
Intestine, small,
duodenum
No.
0
0
0
4
Examined:
Submucosa, bacteria
–
–
–
0
Submucosa, hemorrhage
–
–
–
0
Submucosa, inflammatory
–
–
–
0
infiltrate, neutrophil
Within normal limits
–
–
–
4
Intestine, small,
ileum
No.
Examined:
Submucosa, bacteria
Submucosa, hemorrhage
Submucosa, inflammatory
infiltrate, neutrophil
Within normal limits
Kidneys
No.
Examined:
Glomerular capillaries, bacteria
Glomerular capillaries,
thrombus
Glomerulus, fibrin
Microgranuloma
Pelvis, bacteria
Pelvis, hemorrhage
Pelvis, inflammatory infiltrate,
neutrophil
Tubule, dilatation
Tubule, mineral
Tubulo-interstitial,
inflammation, chronic
Within normal limits
Controls
Treated
2
10
2
1
1
1
0
0
1
0
1
1
0
0
0
0
2
1
–
–
–
–
–
–
–
–
1
1
0
0
–
–
–
–
1
0
–
–
–
–
1
1
10
0
0
4
2
1
0
–
–
0
1
0
–
–
0
1
0
0
1
1
0
0
–
–
–
–
–
–
–
–
0
0
0
0
0
0
1
1
0
–
–
0
1
0
0
–
–
–
–
1
1
0
1
0
1
1
–
–
0
0
0
8
–
–
2
0
0
a
0
0
0
0
0
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Incidence of Neoplastic and Non-Neoplastic Microscopic Findings
Natural History Study
USAMRIID A05-04G
LRRI
BBRC BBRC
USAMRIID
FY06617
875
F03-09G
Tissue/Observation
126
b
c
10
10
10
No. of Animals:
4
Larynx
No.
0
0
0
4
Examined:
Muscularis, myofiber,
–
–
–
2
degeneration
Skeletal muscle, hemorrhage
–
–
–
1
Skeletal muscle, inflammatory
–
–
–
1
infiltrate, neutrophil
Skeletal muscle, myocyte,
–
–
–
1
degeneration
Skeletal muscle, protozoal cyst
–
–
–
2
Skeletal muscle, cellular
–
–
–
1
infiltrate, lymphoplasmacytic
Submucosa, bacteria
–
–
–
0
Submucosa, cellular infiltrate,
–
–
–
1
lymphoplasmacytic
Submucosa, hemorrhage
–
–
–
0
Submucosa, inflammatory
–
–
–
0
infiltrate, neutrophil
Within normal limits
–
–
–
1
Lip
No.
Examined:
Within normal limits
Controls
Treated
2
10
2
1
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
0
1
0
1
0
1
1
0
0
0
4
2
1
–
–
–
4
2
1
a
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Incidence of Neoplastic and Non-Neoplastic Microscopic Findings
Natural History Study
USAMRIID A05-04G
LRRI
BBRC BBRC
USAMRIID
FY06617
875
F03-09G
Tissue/Observation
126
b
c
10
10
10
No. of Animals:
4
Liver
No.
10
–
10
4
Examined:
Bacteria
0
–
1
0
Congestion
0
–
1
0
Hematopoietic cell proliferation
0
–
0
0
Hepatocyte, degeneration,
0
–
0
1
single cell
Hepatocyte, hydropic change
0
–
7
0
Inflammatory infiltrate,
0
–
1
0
neutrophil
Periportal, cellular infiltrate,
0
–
0
2
lymphoplasmacytic
Perivascular, inflammation,
0
–
0
0
chronic
Sinusoids, bacteria
0
–
0
0
Sinusoid, thrombi
0
–
0
1
Within normal limits
10
–
2
1
Lung
No.
Examined:
Alveolus, fibrin
Bacteria
Edema
Fibrosis
Hemorrhage
Inflammation, granulomatous
Inflammatory infiltrate, intraalveolar, macrophage
Inflammatory infiltrate, intraalveolar, neutrophil
Necrosis, multifocal
Pleura, fibrin
Pleura, inflammatory infiltrate,
macrophage
Within normal limits
Controls
Treated
2
10
2
1
0
2
0
0
1
1
0
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
10
10
10
4
2
1
0
10
10
0
8
0
0
10
10
0
9
0
0
9
6
0
10
0
0
4
3
0
4
0
0
2
2
0
2
0
1
1
1
0
1
1
10
6
10
4
2
1
10
6
10
4
1
1
0
3
4
8
0
10
0
3
0
2
0
1
1
0
0
0
0
0
0
0
0
0
0
0
a
64 of 109
Ciprofloxacin
Pre-IND 113289
Incidence of Neoplastic and Non-Neoplastic Microscopic Findings
Natural History Study
USAMRIID A05-04G
LRRI
BBRC BBRC
USAMRIID
FY06617
875
F03-09G
Tissue/Observation
126
b
c
10
10
10
No. of Animals:
4
Lymph node, axillary No.
0
0
0
4
Examined:
Congestion
–
–
–
0
Lymphoid hyperplasia
–
–
–
4
Within normal limits
–
–
–
0
Lymph node, bronchial/
tracheobronchial
No.
Examined:
Bacteria
Edema
Hemorrhage
Inflammatory infiltrate,
neutrophil
Lymphoid depletion
Lymphoid hyperplasia
Within normal limits
Lymph node,
inguinal
No.
Examined:
Sinus histiocytosis
Lymphoid hyperplasia
Within normal limits
Lymph node,
mandibular
No.
Examined:
Bacteria
Congestion
Cyst
Hemorrhage
Inflammatory infiltrate,
neutrophil
Lymphoid depletion
Lymphoid hyperplasia
Perinodal connective tissue,
hemorrhage
Within normal limits
Controls
Treated
2
10
2
1
0
1
1
1
0
0
10
10
10
4
0
0
10
3
8
10
7
6
8
5
3
4
4
1
–
–
–
–
–
–
8
4
4
3
–
–
1
0
0
10
0
0
2
2
0
0
1
0
–
–
–
–
–
–
0
0
0
4
2
1
–
–
–
–
–
–
–
–
–
1
3
0
0
1
1
0
0
1
3
1
0
4
2
1
3
0
0
2
1
0
0
1
–
–
–
–
0
0
0
0
1
0
1
0
0
1
0
0
1
0
–
0
0
0
0
0
1
0
–
–
0
3
0
1
0
0
0
0
–
1
0
0
0
0
–
1
0
0
a
65 of 109
Ciprofloxacin
Pre-IND 113289
Incidence of Neoplastic and Non-Neoplastic Microscopic Findings
Natural History Study
USAMRIID A05-04G
LRRI
BBRC BBRC
USAMRIID
FY06617
875
F03-09G
Tissue/Observation
126
b
c
10
10
10
No. of Animals:
4
Lymph node,
mediastinal
No.
10
10
0
4
Examined:
Bacteria
10
9
–
4
Edema
0
1
–
4
Hemorrhage
5
5
–
1
Inflammatory infiltrate,
7
1
–
4
neutrophil
Lymphoid depletion
0
8
–
0
Lymphoid hyperplasia
0
0
–
1
Within normal limits
0
1
–
0
Lymph node,
mesenteric
No.
Examined:
Bacteria
Hemorrhage
Inflammatory infiltrate,
neutrophil
Lymphoid hyperplasia
Medullary cords, histiocytosis
Within normal limits
Lymph node, other
No.
Examined:
Bacteria
Hemorrhage
Lymphoid hyperplasia
Within normal limits
Mammary gland
and nipple
No.
Examined:
Within normal limits
Controls
Treated
2
10
2
1
2
1
2
0
0
0
2
1
0
0
0
0
0
0
0
0
0
4
2
1
–
–
–
–
–
–
0
0
1
1
–
–
–
0
1
0
0
0
–
–
–
–
–
–
–
–
–
4
0
0
1
0
0
0
1
0
0
2
0
0
0
0
–
–
–
–
1
1
2
0
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
0
0
0
1
0
0
–
–
–
1
–
–
a
66 of 109
Ciprofloxacin
Pre-IND 113289
Incidence of Neoplastic and Non-Neoplastic Microscopic Findings
Natural History Study
USAMRIID A05-04G
LRRI
BBRC BBRC
USAMRIID
FY06617
875
F03-09G
Tissue/Observation
126
b
c
10
10
10
No. of Animals:
4
Mediastinum
No.
0
0
0
4
Examined:
Bacteria
–
–
–
2
Connective tissue, bacteria
–
–
–
0
Connective tissue, edema
–
–
–
3
Connective tissue, hemorrhage
–
–
–
2
Connective tissue,
inflammatory infiltrate,
–
–
–
2
neutrophil
Within normal limits
–
–
–
1
Muscle, skeletal,
quadriceps
No.
Examined:
Hemorrhage
Inflammatory, infiltrate,
mononuclear cell
Inflammatory, infiltrate,
neutrophil
Myocyte, degeneration
Myofiber, protozoal cyst
Within normal limits
Nares
No.
Examined:
Within normal limits
Nerve, sciatic
No.
Examined:
Within normal limits
Oropharynx
No.
Examined:
Within normal limits
Controls
Treated
2
10
1
1
0
1
0
1
0
0
1
0
1
0
0
0
0
0
0
4
2
1
–
–
–
1
0
0
–
–
–
0
0
1
–
–
–
1
0
0
–
–
–
–
–
–
–
–
–
1
2
1
1
0
1
1
0
0
0
0
0
4
2
1
–
–
–
4
2
1
0
0
0
4
2
1
–
–
–
4
2
1
0
0
0
3
0
0
–
–
–
3
–
–
a
67 of 109
Ciprofloxacin
Pre-IND 113289
Incidence of Neoplastic and Non-Neoplastic Microscopic Findings
Natural History Study
USAMRIID A05-04G
LRRI
BBRC BBRC
USAMRIID
FY06617
875
F03-09G
Tissue/Observation
126
b
c
10
10
10
No. of Animals:
4
Ovaries
No.
0
0
0
2
Examined:
Stroma, bacteria
–
–
–
0
Stroma, hemorrhage
–
–
–
0
Stroma, inflammatory infiltrate
–
–
–
0
Within normal limits
–
–
–
2
Oviduct
No.
Examined:
Within normal limits
Pancreas
No.
Examined:
Autolysis precludes diagnosis
Within normal limits
Parathyroid glands
No.
Examined:
Within normal limits
Pituitary gland
No.
Examined:
Within normal limits
Prostate
No.
Examined:
Within normal limits
Salivary gland,
mandibular/
submandibular
No.
Examined:
Cellular infiltrate,
lymphoplasmacytic
Cellular infiltrate, mononuclear
cell
Within normal limits
Controls
Treated
2
10
1
0
1
1
1
0
–
–
–
–
0
0
0
1
0
0
–
–
–
1
–
–
0
0
0
4
2
1
–
–
–
–
–
–
0
4
1
1
1
0
0
0
0
1
2
1
–
–
–
1
2
1
0
0
0
4
2
1
–
–
–
4
2
1
0
0
0
2
1
1
–
–
–
2
1
1
0
0
0
4
2
1
–
–
–
3
0
0
–
–
–
0
1
0
–
–
–
1
1
1
a
68 of 109
Ciprofloxacin
Pre-IND 113289
Incidence of Neoplastic and Non-Neoplastic Microscopic Findings
Natural History Study
USAMRIID A05-04G
LRRI
BBRC BBRC
USAMRIID
FY06617
875
F03-09G
Tissue/Observation
126
b
c
10
10
10
No. of Animals:
4
Skin, haired
No.
0
0
1
4
Examined:
Adnexa, inflammatory
–
–
0
0
infiltrate, neutrophil
Subcutis, bacteria
–
–
0
0
Subcutis, hemorrhage
–
–
0
0
Within normal limits
–
–
1
4
Spleen
No.
Examined:
Bacteria
Congestion
Hemorrhage
Inflammatory infiltrate,
neutrophil
Lymphoid depletion
Plasmacytosis
Within normal limits
Stomach
No.
Examined:
Glandular, submucosa,
hemorrhage
Submucosa, inflammatory
infiltrate, mononuclear cell
Within normal limits
Testes
No.
Examined:
Seminiferous tubule,
degeneration
Within normal limits
Controls
Treated
2
10
2
1
1
0
1
1
1
0
0
1
10
2
10
4
2
1
9
0
4
1
0
2
5
0
5
3
1
0
1
1
0
1
0
7
4
1
0
0
0
0
4
0
0
2
0
0
0
0
1
0
0
0
0
0
0
0
1
0
0
0
1
4
2
1
–
–
1
0
0
0
–
–
0
0
0
0
–
–
0
4
2
1
0
0
0
2
1
1
–
–
–
0
1
0
–
–
–
2
0
1
a
69 of 109
Ciprofloxacin
Pre-IND 113289
Incidence of Neoplastic and Non-Neoplastic Microscopic Findings
Natural History Study
USAMRIID A05-04G
LRRI
BBRC BBRC
USAMRIID
FY06617
875
F03-09G
Tissue/Observation
126
b
c
10
10
10
No. of Animals:
4
Thymus
No.
0
2
0
4
Examined:
Edema
–
2
–
0
Hassal’s corpuscle,
–
0
–
1
degeneration, cystic
Hemorrhage
–
2
–
0
Lymphoid depletion
–
1
–
0
Within normal limits
–
0
–
3
Thyroid glands
No.
Examined:
Within normal limits
Tissue, Not Otherwise
Specified (NOS)
No.
Examined:
Within normal limits
Tongue
No.
Examined:
Cellular infiltrate, mononuclear
cell
Cellular infiltrate,
lymphoplasmacytic
Skeletal muscle, protozoal cyst
Within normal limits
Tonsil
No.
Examined:
Crypt, bacteria
Crypt, inflammatory cells,
neutrophil
Crypt, keratin aggregate
Skeletal muscle, protozoal cyst
Submucosa, hemorrhage
Within normal limits
Controls
Treated
2
10
2
1
0
1
0
0
0
0
2
0
0
0
0
0
0
4
2
1
–
–
–
4
2
1
0
0
1
0
0
0
–
–
1
–
–
–
0
0
0
4
2
1
–
–
–
0
1
0
–
–
–
2
0
0
–
–
–
–
–
–
2
1
0
1
0
1
0
0
0
4
2
1
–
–
–
1
1
0
–
–
–
2
1
0
–
–
–
–
–
–
–
–
–
–
–
–
3
1
1
0
1
0
0
1
0
0
0
1
a
70 of 109
Ciprofloxacin
Pre-IND 113289
Incidence of Neoplastic and Non-Neoplastic Microscopic Findings
Natural History Study
USAMRIID A05-04G
LRRI
BBRC BBRC
USAMRIID
FY06617
875
F03-09G
Tissue/Observation
126
b
c
10
10
10
No. of Animals:
4
Trachea
No.
0
0
0
4
Examined:
Bacteria
–
–
–
0
Connective tissue surrounding
–
–
–
0
trachea, bacteria
Connective tissue surrounding
–
–
–
0
trachea, hemorrhage
Connective tissue surrounding
trachea, inflammatory
–
–
–
0
infiltrate, neutrophil
Epithelium, inflammatory
–
–
–
0
infiltrate, neutrophil
Skeletal muscle, protozoal cyst
–
–
–
1
Skeletal muscle, cellular
–
–
–
1
infiltrate, lymphoplasmacytic
Submucosa, bacteria
–
–
–
1
Submucosa, hemorrhage
–
–
–
0
Submucosa, inflammatory
–
–
–
1
infiltrate, neutrophil
Within normal limits
–
–
–
3
Ureter
No.
Examined:
Within normal limits
Urinary bladder
No.
Examined:
Within normal limits
Uterus
No.
Examined:
Bacteria
Endometrium, hemorrhage
Within normal limits
Controls
Treated
2
10
2
1
0
1
1
0
1
0
1
0
0
1
0
0
0
0
1
1
0
0
1
0
1
0
0
0
0
1
0
0
–
–
–
1
–
–
0
0
0
4
2
1
–
–
–
4
2
1
0
0
0
2
1
0
–
–
–
–
–
–
–
–
–
0
0
2
1
1
0
–
–
–
a
71 of 109
Ciprofloxacin
Pre-IND 113289
Incidence of Neoplastic and Non-Neoplastic Microscopic Findings
Natural History Study
USAMRIID A05-04G
LRRI
BBRC BBRC
USAMRIID
FY06617
875
F03-09G
Tissue/Observation
126
b
c
10
10
10
No. of Animals:
4
Vagina
No.
0
0
0
1
Examined:
Mucosa, cellular infiltrate,
–
–
–
1
lymphoplasmacytic
Within normal limits
–
–
–
0
Vein, large (jugular)
No.
Examined:
Endothelium, ulceration
Thrombus, organizing
Within normal limits
Controls
Treated
2
10
0
0
–
–
–
–
0
0
0
2
0
0
–
–
–
–
–
–
–
–
–
1
1
0
–
–
–
–
–
–
a
– = Not applicable; tissue not examined; BBRC = Battelle Biomedical Research Center; LRRI = Lovelace
Respiratory Research Institute; No. = number; USAMRIID = United States Army Medical Research Institute of
Infectious Diseases
a
Ciprofloxacin treated.
b
c
Number of animals available for microscopic evaluation.
Two animals that received < LD99 challenge dose showed no clinical signs post challenge and survived. They
were not euthanized at study termination.
72 of 109
Ciprofloxacin
Pre-IND 113289
Appendix B
Ciprofloxacin IV Package Insert
73 of 109
CIPRO® I.V.
(ciprofloxacin)
For Intravenous Infusion
7/11
WARNING:
Fluoroquinolones, including CIPRO® I.V., are associated with an increased risk of tendinitis and
tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of
age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants
(see WARNINGS).
Fluoroquinolones, including CIPRO I.V., may exacerbate muscle weakness in persons with
myasthenia gravis. Avoid CIPRO I.V. in patients with known history of myasthenia gravis (see
WARNINGS).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by bacteria.
DESCRIPTION
CIPRO I.V. (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.)
administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1­
piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical
structure is:
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble
in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO I.V.
solutions are available as sterile 1% aqueous concentrates, which are intended for dilution prior to
administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas
contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the
1% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion
solutions is 3.5 to 4.6.
The plastic container is latex-free and is fabricated from a specially formulated polyvinyl chloride.
Solutions in contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per
million. The suitability of the plastic has been confirmed in tests in animals according to USP biological
tests for plastic containers as well as by tissue culture toxicity studies.
NDA 019857 Cipro IV Microbiology Update 06 July 2011
1
74 of 109
Reference ID: 3000237
CLINICAL PHARMACOLOGY
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers,
the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL) After 60-minute I.V. Infusions q 12 h. Dose
200 mg
400 mg
30 min.
1.7
3.7
Time after starting the infusion
1 hr
3 hr
6 hr
2.1
0.6
0.3
4.6
1.3
0.7
8 hr
0.2
0.5
12 hr
0.1
0.2
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q
12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70–80% with no substantial loss
by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every
12 hours has been shown to produce an area under the serum concentration time curve (AUC)
equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400
mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at
steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V.
dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg
ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose
given every 12 hours.
Steady-state Pharmacokinetic Parameter
Following Multiple Oral and I.V. Doses
Parameters
AUC (µg•hr/mL)
Cmax (µg/mL)
500 mg
q12h, P.O.
13.7 a
2.97
400 mg
q12h, I.V.
12.7 a
4.56
750 mg
q12h, P.O.
31.6 b
3.59
400 mg
q8h, I.V.
32.9 c
4.07
a
AUC0-12h
AUC 24h=AUC0-12h × 2
c
AUC 24h=AUC0-8h × 3
b
Distribution
After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions,
sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been
detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal
fluid (CSF), CSF concentrations are generally less than 10% of peak serum concentrations. Levels of
the drug in the aqueous and vitreous chambers of the eye are lower than in serum.
Metabolism
After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine which
together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum
proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2)
NDA 019857 Cipro IV Microbiology Update 06 July 2011
2
75 of 109
Reference ID: 3000237
mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by
CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically
significant adverse events of the coadministered drug (see CONTRAINDICATIONS; WARNINGS;
PRECAUTIONS: Drug Interactions).
Excretion
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr.
After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as
unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 µg/mL
0–2 hours after dosing and are generally greater than 15 µg/mL 8–12 hours after dosing. Following a
400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL 0–2 hours after dosing and are
usually greater than 30 µg/mL 8–12 hours after dosing. The renal clearance is approximately 22 L/hr.
The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose (< 1%) is recovered from the bile as
unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after
dosing.
Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65
years) as compared to young adults. Although the Cmax is increased 16–40%, the increase in mean AUC
is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly.
Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not
considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage
adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in
ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in patients
with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4
months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 – 3.4 µg/mL) and the mean AUC was 9.2
µg*h/mL (range: 5.8 – 14.9 µg*h/mL). There was no apparent age-dependence, and no notable increase
in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were given
intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 –
8.3 µg/mL) in 10 children less than 1 year of age; and 7.2 µg/mL (range: 4.7 – 11.8 µg/mL) in 10
children between 1 and 5 years of age. The AUC values were 17.4 µg*h/mL (range: 11.8 – 32.0
µg*h/mL) and 16.5 µg*h/mL (range: 11.0 – 23.8 µg*h/mL) in the respective age groups. These values
are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic
analysis of pediatric patients with various infections, the predicted mean half-life in children is
approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately 60%.
Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated (See
CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between
ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide,
metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS:
PRECAUTIONS: Drug Interactions.)
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MICROBIOLOGY
Mechanism of Action
The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA
gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair,
and recombination.
Drug Resistance
The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of
penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms
resistant to these classes of drugs may be susceptible to ciprofloxacin and other fluoroquinolones. There
is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. In vitro
resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due
to spontaneous mutations occurs in vitro at a general frequency of between < 10-9 to 1x10-6.
Activity in vitro and in vivo
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive
microorganisms. Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has
little effect when tested in vitro. The minimal bactericidal concentration (MBC) generally does not
exceed the minimal inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in
vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the
package insert for CIPRO I.V. (ciprofloxacin for intravenous infusion).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.) Staphylococcus aureus (methicillin-susceptible strains only) Staphylococcus epidermidis (methicillin-susceptible strains only) Staphylococcus saprophyticus Streptococcus pneumoniae (penicillin-susceptible strains) Streptococcus pyogenes Aerobic gram-negative microorganisms
Citrobacter diversus
Morganella morganii
Citrobacter freundii
Proteus mirabilis
Enterobacter cloacae
Proteus vulgaris
Escherichia coli
Providencia rettgeri
Haemophilus influenzae
Providencia stuartii
Haemophilus parainfluenzae
Pseudomonas aeruginosa
Klebsiella pneumoniae
Serratia marcescens
Moraxella catarrhalis
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum
levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
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The following in vitro data are available, but their clinical significance is unknown. Ciprofloxacin
exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against most (≥ 90%)
strains of the following microorganisms; however, the safety and effectiveness of ciprofloxacin
intravenous formulations in treating clinical infections due to these microorganisms have not been
established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus Staphylococcus hominis Streptococcus pneumoniae (penicillin-resistant strains) Aerobic gram-negative microorganisms
Acinetobacter Iwoffi
Salmonella typhi
Aeromonas hydrophila
Shigella boydii
Campylobacter jejuni
Shigella dysenteriae
Edwardsiella tarda
Shigella flexneri
Enterobacter aerogenes
Shigella sonnei
Klebsiella oxytoca
Vibrio cholerae
Legionella pneumophila
Vibrio parahaemolyticus
Neisseria gonorrhoeae
Vibrio vulnificus
Pasteurella multocida
Yersinia enterocolitica
Salmonella enteritidis
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to
ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.
Susceptibility Tests
• Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of
bacteria to antimicrobial compounds. The MICs should be determined using a standardized
procedure. Standardized procedures are based on a dilution method1 (broth or agar) or
equivalent with standardized inoculum concentrations and standardized concentrations of
ciprofloxacin powder. The MIC values should be interpreted according to the criteria
outlined in Table 1.
• Diffusion Techniques: Quantitative methods that require measurement of zone diameters also
provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One
such standardized procedure2 requires the use of standardized inoculum concentrations. This
procedure uses paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of
microorganisms to ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a
5-µg ciprofloxacin disk should be interpreted according to the criteria outlined in Table 1.
Interpretation involves correlation of the diameter obtained in the disk test with the MIC for
ciprofloxacin.
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Table 1: Susceptibility Interpretive Criteria for Ciprofloxacin
MIC (μg/mL)
Zone Diameter (mm)
Species
S
I
R
S
I
R
Enterobacteriacae
≤1
2
≥4
≥21
16-20
≤15
Enterococcus faecalis
≤1
2
≥4
≥21
16-20
≤15
Methicillin susceptible
Staphylococcus species
Pseudomonas aeruginosa
≤1
2
≥4
≥21
16-20
≤15
≤1
2
≥4
≥21
16-20
≤15
Haemophilus influenzae
≤1a
e
e
≥21b
e
e
Haemophilus parainfluenzae
≤1a
e
e
≥21b
e
e
Penicillin susceptible
Streptococcus pneumoniae
≤1c
2c
≥4c
≥21d
16-20d
≤15d
Streptococcus pyogenes
≤1c
2c
≥4c
≥21d
16-20d
≤15d
S=susceptible, I=Intermediate, and R=resistant.
This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus
influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)1.
b
This zone diameter standard is applicable only to tests with Haemophilus influenzae using Haemophilus Test
Medium (HTM)3.
c
These interpretive standards are applicable only to broth microdilution susceptibility tests with
streptococci using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
d
These zone diameter standards are applicable only to tests performed for streptococci using Mueller-Hinton agar
supplemented with 5% sheep blood incubated in 5% CO2.
e
The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding
zone diameter results suggestive of a “Non-Susceptible” category should be submitted to a reference laboratory for
further testing.
a
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the microorganism is not fully
susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies
possible clinical applicability in body sites where the drug is physiologically concentrated or in
situations where high dosage of drug can be used. This category also provides a buffer zone, which
prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A
report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
• Quality Control: Standardized susceptibility test procedures require the use of laboratory control
microorganisms to control the technical aspects of the laboratory procedures. For dilution
technique, standard ciprofloxacin powder should provide the following MIC values: standard
ciprofloxacin powder should give the MIC values provided in Table 2. For diffusion technique, the
5-µg ciprofloxacin disk should provide the zone diameters outlined in Table 2.
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Table 2: Quality Control for Susceptibility Testing
MIC range (μg/mL)
Zone Diameter
(mm)
0.25–2
-
Escherichia coli ATCC 25922
0.004–0.015
30–40
Haemophilus influenzae ATCC 49247
0.004–0.03a
34–42b
0.25–1
25–33
Staphylococcus aureus ATCC29213
0.12–0.5
-
Staphylococcus aureus ATCC25923
-
22–30
Strains
Enterococcus faecalis ATCC 29212
Pseudomonas aeruginosa ATCC 27853
a
This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution
procedure using Haemophilus Test Medium (HTM)1.
b
These quality control limits are applicable to only H. influenzae ATCC 49247 testing using Haemophilus
Test Medium (HTM)3.
INDICATIONS AND USAGE
CIPRO I.V. is indicated for the treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below when the intravenous
administration offers a route of administration advantageous to the patient. Please see DOSAGE AND
ADMINISTRATION for specific recommendations.
Adult Patients:
Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus
mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii,
Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus
saprophyticus, or Enterococcus faecalis.
Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus
influenzae, Haemophilus parainfluenzae, or penicillin-susceptible 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.
Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae. Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii,
Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus pyogenes. Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas NDA 019857 Cipro IV Microbiology Update 06 July 2011
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aeruginosa.
Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by
Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides
fragilis.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae,
or Moraxella catarrhalis.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See
CLINICAL STUDIES.)
Pediatric patients (1 to 17 years of age):
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use,
ADVERSE REACTIONS and CLINICAL STUDIES.) Ciprofloxacin, like other fluoroquinolones, is
associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals.
(See ANIMAL PHARMACOLOGY.)
Adult and Pediatric Patients:
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably
likely to predict clinical benefit and provided the initial basis for approval of this indication.4
Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained
during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL ANTHRAX –
ADDITIONAL INFORMATION).
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be
administered.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and
identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with
CIPRO I.V. may be initiated before results of these tests are known; once results become available,
appropriate therapy should be continued.
As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly
during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on
the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO I.V. and
other antibacterial drugs, CIPRO I.V. should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information
are available, they should be considered in selecting or modifying antibacterial therapy. In the absence
of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
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CONTRAINDICATIONS
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any
member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug
Interactions.)
WARNINGS
Tendinopathy and Tendon Rupture: Fluoroquinolones, including CIPRO I.V., are associated with an
increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently
involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis
and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon
sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon
rupture is further increased in older patients usually over 60 years of age, in patients taking
corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age
and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous
physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis
and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above
risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to
several months after completion of therapy have been reported. CIPRO I.V. should be discontinued if
the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised
to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding
changing to a non-quinolone antimicrobial drug.
Exacerbation of Myasthenia Gravis: Fluoroquinolones, including CIPRO I.V., have neuromuscular
blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis.
Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have
been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid CIPRO in patients
with known history of myasthenia gravis. (See PRECAUTIONS: Information for Patients and
ADVERSE REACTIONS: Post-Marketing Adverse Event Reports).
Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN
PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)
Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for
infections listed in the INDICATIONS AND USAGE section. An increased incidence of adverse
events compared to controls, including events related to joints and/or surrounding tissues, has been
observed. (See ADVERSE REACTIONS.)
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs.
Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of
the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints
and other signs of arthropathy in immature animals of various species. (See ANIMAL
PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.
Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g.
theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the
coadministered drug and could lead to clinically significant pharmacodynamic side effects of the
coadministered drug.
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Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic psychosis
have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also
cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations,
depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If
these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and
appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in
patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure
threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that
may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy, renal dysfunction).
(See PRECAUTIONS: General, Information for Patients, Drug Interaction and ADVERSE
REACTIONS.)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS CIPROFLOXACIN
AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and
respiratory failure. Although similar serious adverse events have been reported in patients receiving
theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be
eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and
dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
some following the first dose, have been reported in patients receiving quinolone therapy. Some
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or
facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and
other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management, as clinically indicated.
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain
etiology, have been reported rarely in patients receiving therapy with quinolones, including
ciprofloxacin. These events may be severe and generally occur following the administration of multiple
doses. Clinical manifestations may include one or more of the following:
• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis,
• Stevens-Johnson syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic
thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic
abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any
other sign of hypersensitivity and supportive measures instituted (see PRECAUTIONS: Information
for Patients and ADVERSE REACTIONS).
Pseudomembranous Colitis: Clostridium difficile associated diarrhea (CDAD) has been reported with
use of nearly all antibacterial agents, including CIPRO, and may range in severity from mild diarrhea to
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fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to
overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing strains of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all
patients who present with diarrhea following antibiotic use. Careful medical history is necessary since
CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
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 ciprofloxacin. Ciprofloxacin should be
discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling,
numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense,
vibratory sensation, and/or motor strength in order to prevent the development of an irreversible
condition.
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with the
intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30
minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)
Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous system
(CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See
WARNINGS, Information for Patients, and Drug Interactions.)
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently
in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is
usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly concentrated urine.
Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment of renal
function. (See DOSAGE AND ADMINISTRATION.)
Photosensitivity/Phototoxicity: Moderate to severe photosensitivity/phototoxicity reactions, the latter
of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles,
blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor
surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or
UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug
therapy should be discontinued if phototoxicity occurs (See ADVERSE REACTIONS/
Post-Marketing Adverse Events).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy.
Prescribing CIPRO I.V. in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
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Information For Patients:
Patients should be advised:
• to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon,
or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue
CIPRO I.V. treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older
patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with
kidney, heart or lung transplants.
• that fluoroquinolones like CIPRO I.V. may cause worsening of myasthenia gravis symptoms,
including muscle weakness and breathing problems. Patients should call their healthcare provider
right away if they have any worsening muscle weakness or breathing problems.
• that antibacterial drugs including CIPRO I.V. should only be used to treat bacterial infections. They
do not treat viral infections (e.g., the common cold). When CIPRO I.V. is prescribed to treat a
bacterial infection, patients should be told that although it is common to feel better early in the
course of therapy, the medication should be taken exactly as directed. Skipping doses or not
completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment
and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by
CIPRO I.V. or other antibacterial drugs in the future.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
• that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients
should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B
treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they
should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun
protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients
should contact their physician.
• that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how
they react to this drug before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
• that ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use
ciprofloxacin if they are already taking tizanidine.
• that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of
caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.
• that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral
neuropathy including pain, burning, tingling, numbness and/or weakness develop, they should
discontinue treatment and contact their physicians.
• that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
• that ciprofloxacin has been associated with an increased rate of adverse events involving joints and
surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents
should inform their child’s physician if the child has a history of joint-related problems before
taking this drug. Parents of pediatric patients should also notify their child’s physician of any
joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS,
PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.)
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• that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is
discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and
bloody stools (with or without stomach cramps and fever) even as late as two or more months after
having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as
soon as possible.
Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was
significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also
potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
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. This may
result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant
use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made
as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of
caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum
creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs
were given concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant
warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or
other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level
of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs
concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the
risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should
be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses
of quinolones have been shown to provoke convulsions in pre-clinical studies.
Following infusion of 400 mg I.V. ciprofloxacin every eight hours in combination with 50 mg/kg I.V.
piperacillin sodium every four hours, mean serum ciprofloxacin concentrations were 3.02 µg/mL 1/2
hour and 1.18 µg/mL between 6–8 hours after the end of infusion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been
conducted with ciprofloxacin. Test results are listed below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
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Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three in vivo test systems gave
negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects
due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively
(approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to
appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were
exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently
being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum
recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with
both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice
treated concomitantly with UVA and other quinolones.4
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are
no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of
these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately
0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of
impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled
studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use
during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses
during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair),
but the data are insufficient to state that there is no risk.8
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.9 In utero exposure to fluo­
roquinolones during embryogenesis was not associated with increased risk of major malformations. The
reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1-5%). Rates of spontaneous
abortions, prematurity and low birth weight did not differ between the groups and there were no
clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed
children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93%
first trimester exposures).10 There were 70 ciprofloxacin exposures, all within the first trimester. The
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malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall
were both within background incidence ranges. No specific patterns of congenital abnormalities were
found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women
exposed to ciprofloxacin during pregnancy.8,9 However, these small postmarketing epidemiology
studies, of which most experience is from short term, first trimester exposure, are insufficient to
evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the
safety of ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be
used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother
(see WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and
0.3 times the maximum daily human dose based upon body surface area, respectively) and have
revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels
of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose
based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased
incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous
administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic
dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity
was observed. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by
the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in
weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL
PHARMACOLOGY.)
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit
assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate. For
information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND
ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis
due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not a drug of first choice in
the pediatric population due to an increased incidence of adverse events compared to the controls,
including those related to joints and/or surrounding tissues. The rates of these events in pediatric
patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were
9.3% (31/335) versus 6.0% (21/349) for control agents. The rates of these events occurring at any time
up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all
adverse events regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm
compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Cystic Fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a
randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic
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fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one
week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62
patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3
mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not studied. Safety
monitoring in the study included periodic range of motion examinations and gait assessments by
treatment-blinded examiners. Patients were followed for an average of 23 days after completing
treatment (range 0-93 days). This study was not designed to determine long term effects and the safety
of repeated exposure to ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in
the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in
12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was
reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other
adverse events were similar in nature and frequency between treatment arms. One of sixty-seven
patients developed arthritis of the knee nine days after a ten day course of treatment with ciprofloxacin.
Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight
months after treatment. However, the relationship of this event to the patient’s course of ciprofloxacin
can not be definitively determined, particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as part of their underlying disease process.
Geriatric Use: Geriatric patients are at increased risk for developing severe tendon disorders including
tendon rupture when being treated with a fluoroquinolone such as CIPRO I.V. This risk is further
increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can
involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of
therapy; cases occurring up to several months after fluoroquinolone treatment have been reported.
Caution should be used when prescribing CIPRO I.V. to elderly patients especially those on
corticosteroids. Patients should be informed of this potential side effect and advised to discontinue
CIPRO I.V. and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur
(See Boxed Warning, WARNINGS, and ADVERSE REACTIONS/Post-Marketing Adverse
Event Reports).
In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing
over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age
and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported clinical experience has
not identified differences in responses between the elderly and younger patients, but greater sensitivity
of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be
substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with
impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age
with normal renal function. However, since some older individuals experience reduced renal function
by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal
function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and
DOSAGE AND ADMINISTRATION.)
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using CIPRO with concomitant drugs that can result in
prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors
for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
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ADVERSE REACTIONS
Adverse Reactions in Adult Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were
described as only mild or moderate in severity, abated soon after the drug was discontinued, and
required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1.8% of
intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all
drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea
(1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater than 1%
of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous system disturbance,
local I.V. site reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash.
Many of these events were described as only mild or moderate in severity, abated soon after the drug
was discontinued, and required no treatment. Local I.V. site reactions are more frequent if the infusion
time is 30 minutes or less. These may appear as local skin reactions which resolve rapidly upon
completion of the infusion. Subsequent intravenous administration is not contraindicated unless the
reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of administration,
that occurred in 1% or less of ciprofloxacin patients are listed below:
BODY AS A WHOLE: abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest, myocardial infarction,
arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur, hypertension,
hypotension, angina pectoris, atrial flutter, ventricular ectopy, (thrombo)-phlebitis, vasodilation,
migraine
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis, depression,
dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion,
hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares,
weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal convulsion, anorexia
GASTROINTESTINAL: ileus, jaundice, gastrointestinal bleeding, C. difficile associated diarrhea,
pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation, dyspepsia, epigastric
pain, constipation, oral ulceration, oral candidiasis, mouth dryness, anorexia, dysphagia, flatulence,
hepatitis, painful oral mucosa
HEMIC/LYMPHATIC: agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain,
achiness, flare up of gout, myasthenia gravis
RENAL/UROGENITAL: renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis, renal
calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention, gynecomastia,
candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and albuminuria have also been
reported.
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary edema,
respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
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SKIN/HYPERSENSITIVITY: allergic reactions, anaphylactic reactions including life-threatening
anaphylactic shock, erythema multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic
epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae, hands or
lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis, vesicles,
increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia,
erythema, swelling, photosensitivity/phototoxicity reaction (See WARNINGS.)
SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed vision (flashing lights, change
in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus,
nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of drug interaction with
ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin (I.V. and I.V./P.O.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs.
Adverse Reactions in Pediatric Patients: Ciprofloxacin, administered I.V. and /or orally, was
compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was
conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The
duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88
days). The primary objective of the study was to assess musculoskeletal and neurological safety within
6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349
comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse
events as well as all patients with an abnormal gait or abnormal joint exam (baseline or
treatment-emergent). These events were evaluated in a comprehensive fashion and included such
conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis,
bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints
included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates
of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6.0 % (21/349) in
comparator-treated patients. The majority of these events were mild or moderate in intensity. All
musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms),
usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm
resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients than
control patients, regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients
were more likely to report more than one event and on more than one occasion compared to control
patients. These events occurred in all age groups and the rates were consistently higher in the
ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events reported
at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5%
(33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An
MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse
syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be
excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
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Ciprofloxacin
All Patients (within 6 weeks)
95% Confidence Interval*
Age Group
≥ 12 months < 24 months
≥ 2 years < 6 years
≥ 6 years < 12 years
≥ 12 years to 17 years
All Patients (within 1 year)
95% Confidence Interval*
Comparator
31/335 (9.3%)
21/349 (6%)
(-0.8%, +7.2%)
1/36 (2.8%)
5/124 (4.0%)
18/143 (12.6%)
7/32 (21.9%)
0/41
3/118 (2.5%)
12/153 (7.8%)
6/37 (16.2 %)
46/335 (13.7%)
33/349 (9.5%)
(-0.6%, +9.1%)
*The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not
exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95%
confidence interval indicated that it could not be concluded that the ciprofloxacin group had findings
comparable to the control group.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the
ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness, nervousness,
insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and
within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31%
(109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of
ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events were
seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients.
Discontinuation of drug due to an adverse event was observed in 3% (10/335) of ciprofloxacin-treated
patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at least 1% of
ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury
3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events
reported in adults during clinical trials or post-marketing experience may also occur in pediatric
patients.
Post-Marketing Adverse Event Reports: The following adverse events have been reported from
worldwide marketing experience with flouroquinolones, including ciprofloxacin. Because these events
are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure. Decisions to include these events in
labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2)
frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed
eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure (including fatal
cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice,
marrow depression (life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal),
myalgia, myasthenia, exacerbation of myasthenia gravis, myoclonus, nystagmus, pancreatitis,
pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration (serum),
photosensitivity/phototoxicity reaction, potassium elevation (serum), prothrombin time prolongation or
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decrease, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur
during or after antimicrobial treatment), psychosis (toxic), renal calculi, serum sickness like reaction,
Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal
necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, and
vasculitis. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax post-exposure
prophylaxis following the anthrax bioterror attacks of October 2001 (See also INHALATIONAL
ANTHRAXADDITIONAL INFORMATION).
Adverse Laboratory Changes: The most frequently reported changes in laboratory parameters with
intravenous ciprofloxacin therapy, without regard to drug relationship are listed below:
Hepatic
elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum
bilirubin
Hematologic elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or
hematocrit
Renal
elevations of serum creatinine, BUN, and uric acid
Other elevations of serum creatine phosphokinase, serum theophylline (in patients receiving
theophylline concomitantly), blood glucose, and triglycerides
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte
count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (γ
GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation of serum amylase, decrease of
blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin,
decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
OVERDOSAGE
In the event of acute overdosage, the patient should be carefully observed and given supportive
treatment, including monitoring of renal function. Adequate hydration must be maintained. Only a
small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal
dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at
intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
DOSAGE AND ADMINISTRATIONADULTS
CIPRO I.V. should be administered to adults by intravenous infusion over a period of 60 minutes at
dosages described in the Dosage Guidelines table. Slow infusion of a dilute solution into a larger vein
will minimize patient discomfort and reduce the risk of venous irritation. (See Preparation of CIPRO
I.V. for Administration section.)
The determination of dosage for any particular patient must take into consideration the severity and
nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s
host-defense mechanisms, and the status of renal and hepatic function.
ADULT DOSAGE GUIDELINES
Infection†
Severity
Dose
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Urinary Tract
Mild/Moderate
Severe/Complicated
200 mg
400 mg
q12h
q12h
7-14 Days
7-14 Days
Lower
Respiratory Tract
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
7-14 Days
7-14 Days
Nosocomial
Pneumonia
Mild/Moderate/Severe
400 mg
q8h
10-14 Days
Skin and
Skin Structure
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
7-14 Days
7-14 Days
Bone and Joint
Mild/Moderate
Severe/Complicated
400 mg
400 mg
q12h
q8h
≥ 4-6 Weeks
≥ 4-6 Weeks
Intra-Abdominal*
Complicated
400 mg
q12h
7-14 Days
Acute Sinusitis
Mild/Moderate
400 mg
q12h
10 Days
Chronic Bacterial
Prostatitis
Mild/Moderate
400 mg
q12h
28 Days
Empirical Therapy
in
Febrile Neutropenic
Patients
Severe
400 mg
q8h
50 mg/kg
Not to exceed
24 g/day
q4h
400 mg
q12h
Inhalational anthrax
(post-exposure)**
Ciprofloxacin
+
Piperacillin
7-14 Days
60 Days
*used in conjunction with metronidazole. (See product labeling for prescribing information.)
†DUE TO THE DESIGNATED PATHOGENS (See INDICATIONS AND USAGE.)
**Drug administration should begin as soon as possible after suspected or confirmed exposure. This
indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.5 For a discussion of ciprofloxacin serum concentrations in
various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL
INFORMATION. Total duration of ciprofloxacin administration (I.V. or oral) for inhalational anthrax
(post-exposure) is 60 days.
CIPRO I.V. should be administered by intravenous infusion over a period of 60 minutes.
Conversion of I.V. to Oral Dosing in Adults: CIPRO Tablets and CIPRO Oral Suspension for oral
administration are available. Parenteral therapy may be switched to oral CIPRO when the condition
warrants, at the discretion of the physician. (See CLINICAL PHARMACOLOGY and table below for
the equivalent dosing regimens.)
Equivalent AUC Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO I.V. Dosage
250 mg Tablet q 12 h
200 mg I.V. q 12 h
500 mg Tablet q 12 h
400 mg I.V. q 12 h
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750 mg Tablet q 12 h
400 mg I.V. q 8 h
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
Adults with Impaired Renal Function: Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary system of the liver and
through the intestine. These alternative pathways of drug elimination appear to compensate for the
reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is
recommended for patients with severe renal dysfunction. The following table provides dosage
guidelines for use in patients with renal impairment:
RECOMMENDED STARTING AND MAINTENANCE DOSES FOR PATIENTS WITH IMPAIRED RENAL FUNCTION Creatinine Clearance (mL/min)
Dosage
> 30
See usual dosage.
5 - 29
200-400 mg q 18-24 hr
When only the serum creatinine concentration is known, the following formula may be used to
estimate creatinine clearance:
Weight (kg) × (140 – age)
Men: Creatinine clearance (mL/min) =
72 × serum creatinine (mg/dL)
Women: 0.85 × the value calculated for men.
The serum creatinine should represent a steady state of renal function.
For patients with changing renal function or for patients with renal impairment and hepatic
insufficiency, careful monitoring is suggested.
DOSAGE AND ADMINISTRATIONPEDIATRICS
CIPRO I.V. should be administered as described in the Dosage Guidelines table. An increased incidence
of adverse events compared to controls, including events related to joints and/or surrounding tissues,
has been observed. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or
pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric
patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and
allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
Infection
Complicated
Urinary Tract
or
Pyelonephritis
PEDIATRIC DOSAGE GUIDELINES
Route of
Dose
Frequency
Administratio
(mg/kg)
n
Intravenous
6 to 10 mg/kg
(maximum 400 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
NDA 019857 Cipro IV Microbiology Update 06 July 2011
Total
Duration
Every 8
hours
10-21 days*
22
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Reference ID: 3000237
(patients from
1 to 17 years of
age)
Oral
Inhalational
Anthrax
(Post-Exposure
)**
Intravenous
Oral
10 mg/kg to 20 mg/kg
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
10 mg/kg
(maximum 400 mg per
dose)
Every 12
hours
15 mg/kg
(maximum 500 mg per
dose)
Every 12
hours
Every 12
hours
60 days
* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical
trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21
days).
**
Drug administration should begin as soon as possible after suspected or confirmed exposure to
Bacillus anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum
concentrations achieved in humans, reasonably likely to predict clinical benefit.5 For a discussion of
ciprofloxacin serum concentrations in various human populations, see INHALATIONAL ANTHRAX
– ADDITIONAL INFORMATION.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of
complicated urinary tract infection and pyelonephritis. No information is available on dosing
adjustments necessary for pediatric patients with moderate to severe renal insufficiency (i.e., creatinine
clearance of < 50 mL/min/1.73m2).
Preparation of CIPRO I.V. for Administration
Vials (Injection Concentrate): THIS PREPARATION MUST BE DILUTED BEFORE USE. The
intravenous dose should be prepared by aseptically withdrawing the concentrate from the vial of CIPRO
I.V. This should be diluted with a suitable intravenous solution to a final concentration of 1–2mg/mL.
(See COMPATIBILITY AND STABILITY.) The resulting solution should be infused over a period
of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may already be in
place.
If the Y-type or “piggyback” method of administration is used, it is advisable to discontinue temporarily
the administration of any other solutions during the infusion of CIPRO I.V. If the concomitant use of
CIPRO I.V. and another drug is necessary each drug should be given separately in accordance with the
recommended dosage and route of administration for each drug.
Flexible Containers: CIPRO I.V. is also available as a 0.2% premixed solution in 5% dextrose in
flexible containers of 100 mL or 200 mL. The solutions in flexible containers do not need to be diluted
and may be infused as described above.
COMPATIBILITY AND STABILITY
Ciprofloxacin injection 1% (10 mg/mL), when diluted with the following intravenous solutions to
concentrations of 0.5 to 2.0 mg/mL, is stable for up to 14 days at refrigerated or room temperature
storage.
0.9% Sodium Chloride Injection, USP
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5% Dextrose Injection, USP
Sterile Water for Injection
10% Dextrose for Injection
5% Dextrose and 0.225% Sodium Chloride for Injection
5% Dextrose and 0.45% Sodium Chloride for Injection
Lactated Ringer’s for Injection
HOW SUPPLIED
CIPRO I.V. (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. CIPRO I.V.
is available in 200 mg and 400 mg strengths. The concentrate is supplied in vials while the premixed
solution is supplied in latex-free flexible containers as follows:
VIAL: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by Bayer HealthCare LLC, Shawnee,
Kansas.
SIZE
20 mL
40 mL
STRENGTH
200 mg, 1%
400 mg, 1%
NDC NUMBER
0085-1763-03
0085-1731-01
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by
Hospira, Inc., Lake Forest, IL 60045.
SIZE
STRENGTH
NDC NUMBER
100 mL 5% Dextrose
200 mg, 0.2%
0085-1755-02
200 mL 5% Dextrose
400 mg, 0.2%
0085-1741-02
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc. by
Baxter Healthcare Corporation, Deerfield, IL 60015.
SIZE
100 mL 5% Dextrose
200 mL 5% Dextrose
STRENGTH
200 mg, 0.2%
400 mg, 0.2%
NDC NUMBER
0085-1781-01
0085-1762-01
FLEXIBLE CONTAINER: Manufactured for Bayer HealthCare Pharmaceuticals Inc.
Manufactured in Germany or Norway.
SIZE
100 mL 5% Dextrose
200 mL 5% Dextrose
STRENGTH
200 mg, 0.2%
400 mg, 0.2%
NDC NUMBER
0085-1759-01
0085-1782-01
STORAGE
Vial:
Store between 5 – 30ºC (41 – 86ºF). Flexible Container: Store between 5 – 25ºC (41 – 77ºF). Protect from light, avoid excessive heat, protect from freezing. Ciprofloxacin is also available as CIPRO (ciprofloxacin HCl) Tablets 250, 500, and 750 mg and CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension. NDA 019857 Cipro IV Microbiology Update 06 July 2011
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* Does not comply with USP with regards to “loss on drying” and “residue on ignition”.
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most
species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and
rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular
changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in
young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately
1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks
caused articular changes which were still observed by histopathology after a treatment-free period of 5
months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma
AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after
an additional treatment-free period of 5 months. In another study, removal of weight bearing from the
joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed
with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine
is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral
doses as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based
upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes
were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration
(approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces
pronounced hypotensive effects. These effects are considered to be related to histamine release because
they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous
injection also produces hypotension, but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone
and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of
quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated animals.
INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement
in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and
pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND
ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human
populations.The mean peak serum concentration achieved at steady-state in human adults receiving 500
mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every 12
hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL. In
a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration
achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two
30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous
infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6
µg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the
administration of ciprofloxacin to pediatric patients are limited. (For additional information, see
NDA 019857 Cipro IV Microbiology Update 06 July 2011
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PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a
surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.5
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50
(~5.5 x 105) spores (range 5–30 LD50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the
animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour
post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 µg/mL. Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL6. Mortality due to anthrax
for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was
significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one
ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration
period.7
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic
prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was
recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons
were also given anthrax vaccine or were switched to alternative antibiotics. No one who received
ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax.
The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis
regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000 reported
receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax. Gastrointestinal
adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological adverse events (problems
sleeping, nightmares, headache, dizziness or lightheadedness) and musculoskeletal adverse events
(muscle or tendon pain and joint swelling or pain) were more frequent than had been previously
reported in controlled clinical trials. This higher incidence, in the absence of a control group, could be
explained by a reporting bias, concurrent medical conditions, other concomitant medications, emotional
stress or other confounding factors, and/or a longer treatment period with ciprofloxacin. Because of
these factors and limitations in the data collection, it is difficult to evaluate whether the reported
symptoms were drug-related.
CLINICAL STUDIES
EMPIRICAL THERAPY IN ADULT FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination with piperacillin sodium, 50
mg/kg I.V. q 4h, for the empirical therapy of febrile neutropenic patients were studied in one large
pivotal multicenter, randomized trial and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in
combination with piperacillin sodium, 50 mg/kg I.V. q 4h.
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Clinical response rates observed in this study were as follows:
Outcomes
Clinical Resolution of
Initial Febrile Episode with No Modifications of Empirical Regimen* Clinical Resolution of
Ciprofloxacin/Piperacillin
N = 233
Success (%)
63 (27.0%)
Tobramycin/Piperacillin
N = 237
Success (%)
52 (21.9%) 187
(80.3%)
185
(78.1%)
224
(96.1%)
223
(94.1%)
Initial Febrile Episode Including Patients with Modifications of Empirical Regimen Overall Survival
* To be evaluated as a clinical resolution, patients had to have: (1) resolution of fever; (2)
microbiological eradication of infection (if an infection was microbiologically documented); (3)
resolution of signs/symptoms of infection; and (4) no modification of empirical antibiotic regimen.
Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients:
NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric
population due to an increased incidence of adverse events compared to controls, including events
related to joints and/or surrounding tissues.
Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment of
complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age
(mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica,
Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of
treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s)
with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per
Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no
protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown below.
Clinical Success and Bacteriologic Eradication at Test of Cure
(5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days
95.7% (202/211)
92.6% (214/231)
Post-Treatment
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient
84.4% (178/211)
78.3% (181/231)
at 5 to 9 Days Post-Treatment*
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95% CI [ -1.3%, 13.1%]
Bacteriologic Eradication of the
Baseline Pathogen at 5 to 9 Days
Post-Treatment
Escherichia coli
156/178 (88%)
161/179 (90%)
* Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of
patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with
superinfections or new infections.
References:
1. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests
for Bacteria That Grow Aerobically; Approved Standard – Eighth Edition. CLSI Document M7-A8,
Vol. 29, No. 2, CLSI, Wayne, PA, January, 2009.
2. Clinical and Laboratory Standards Institute. Methods for Antimicrobial Dilution and Disk
Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline – Second
Edition. CLSI Document M45-A2, CLSI, Wayne, PA, January, 2010.
3. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk
Susceptibility Tests; Approved Standard – Tenth Edition. CLSI Document M2-A10, Vol. 29, No. 1,
CLSI, Wayne, PA, January, 2009.
4. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Products Advisory
Committee Meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors
and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA.
5. 21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses).
6. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged
therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7.
7. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect
Dis 1993; 167: 1239-42.
8. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore,
Maryland: Johns Hopkins University Press, 2000:149-195.
9. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to
fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother.
1998;42(6): 1336-1339.
10. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure.
Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J
Obstet Gynecol Reprod Biol. 1996; 69: 83-89.
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MEDICATION GUIDE
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride) TABLETS CIPRO® (Sip-row)
(ciprofloxacin) ORAL SUSPENSION CIPRO® XR (Sip-row)
(ciprofloxacin extended-release tablets) CIPRO® I.V. (Sip-row)
(ciprofloxacin) For Intravenous Infusion READ THE MEDICATION GUIDE THAT COMES WITH CIPRO® BEFORE YOU START TAKING IT AND EACH
TIME YOU GET A REFILL. THERE MAY BE NEW INFORMATION. THIS MEDICATION GUIDE DOES NOT TAKE
THE PLACE OF TALKING TO YOUR HEALTHCARE PROVIDER ABOUT YOUR MEDICAL CONDITION OR YOUR
TREATMENT.
What is the most important information I should know about CIPRO?
CIPRO BELONGS TO A CLASS OF ANTIBIOTICS CALLED FLUOROQUINOLONES. CIPRO CAN CAUSE SIDE
EFFECTS THAT MAY BE SERIOUS OR EVEN CAUSE DEATH. IF YOU GET ANY OF THE FOLLOWING
SERIOUS SIDE EFFECTS, GET MEDICAL HELP RIGHT AWAY. TALK WITH YOUR HEALTHCARE PROVIDER
ABOUT WHETHER YOU SHOULD CONTINUE TO TAKE CIPRO.
1. Tendon rupture or swelling of the tendon (tendinitis)
• Tendon problems can happen in people of all ages who take CIPRO. Tendons are
tough cords of tissue that connect muscles to bones. Symptoms of tendon problems
may include:
• Pain, swelling, tears and inflammation of tendons including the back of the ankle
(Achilles), shoulder, hand, or other tendon sites.
• The risk of getting tendon problems while you take CIPRO is higher if you:
• are over 60 years of age
• are taking steroids (corticosteroids)
• have had a kidney, heart or lung transplant
• Tendon problems can happen in people who do not have the above risk
factors when they take CIPRO. Other reasons that can increase your risk of
tendon problems can include:
• physical activity or exercise
• kidney failure
• tendon problems in the past, such as in people with rheumatoid arthritis (RA)
• Call your healthcare provider right away at the first sign of tendon pain, swelling or
inflammation. Stop taking CIPRO until tendinitis or tendon rupture has been ruled out by
your healthcare provider. Avoid exercise and using the affected area. The most common
area of pain and swelling is the Achilles tendon at the back of your ankle. This can also
happen with other tendons.
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• Talk to your healthcare provider about the risk of tendon rupture with continued use
of CIPRO. You may need a different antibiotic that is not a fluoroquinolone to treat your
infection.
• Tendon rupture can happen while you are taking or after you have finished taking
CIPRO. Tendon ruptures have happened up to several months after patients have
finished taking their fluoroquinolone.
• Get medical help right away if you get any of the following signs or symptoms of a
tendon rupture:
• hear or feel a snap or pop in a tendon area
• bruising right after an injury in a tendon area
• unable to move the affected area or bear weight
2. WORSENING OF MYASTHENIA GRAVIS (A DISEASE WHICH CAUSES MUSCLE WEAKNESS).
FLUOROQUINOLONES LIKE CIPRO MAY CAUSE WORSENING OF MYASTHENIA GRAVIS SYMPTOMS,
INCLUDING MUSCLE WEAKNESS AND BREATHING PROBLEMS. CALL YOUR HEALTHCARE PROVIDER
RIGHT AWAY IF YOU HAVE ANY WORSENING MUSCLE WEAKNESS OR BREATHING PROBLEMS.
SEE THE SECTION “WHAT ARE THE POSSIBLE SIDE EFFECTS OF CIPRO?” FOR MORE INFORMATION
ABOUT SIDE EFFECTS.
What is CIPRO?
CIPRO is a fluoroquinolone antibiotic medicine used to treat certain infections caused
by certain germs called bacteria.
Children less than 18 years of age have a higher chance of getting bone, joint, or
tendon (musculoskeletal) problems such as pain or swelling while taking CIPRO.
CIPRO should not be used as the first choice of antibiotic medicine in children under 18
years of age.
CIPRO Tablets, CIPRO Oral Suspension and CIPRO I.V. should not be used in children
under 18 years old, except to treat specific serious infections, such as complicated
urinary tract infections and to prevent anthrax disease after breathing the anthrax
bacteria germ (inhalational exposure). It is not known if CIPRO XR is safe and works in
children under 18 years of age.
SOMETIMES INFECTIONS ARE CAUSED BY VIRUSES RATHER THAN BY BACTERIA. EXAMPLES INCLUDE
VIRAL INFECTIONS IN THE SINUSES AND LUNGS, SUCH AS THE COMMON COLD OR FLU. ANTIBIOTICS,
INCLUDING CIPRO, DO NOT KILL VIRUSES.
CALL YOUR HEALTHCARE PROVIDER IF YOU THINK YOUR CONDITION IS NOT GETTING BETTER WHILE
YOU ARE TAKING CIPRO.
Who should not take CIPRO?
DO NOT TAKE CIPRO IF YOU:
• HAVE EVER HAD A SEVERE ALLERGIC REACTION TO AN ANTIBIOTIC KNOWN AS A
FLUOROQUINOLONE, OR ARE ALLERGIC TO ANY OF THE INGREDIENTS IN CIPRO. ASK YOUR
HEALTHCARE PROVIDER IF YOU ARE NOT SURE. SEE THE LIST OF INGREDIENTS IN CIPRO AT THE
END OF THIS MEDICATION GUIDE.
®
• ALSO TAKE A MEDICINE CALLED TIZANIDINE (ZANAFLEX ). SERIOUS SIDE EFFECTS FROM
TIZANIDINE ARE LIKELY TO HAPPEN.
What should I tell my healthcare provider before taking CIPRO? SEE “WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT CIPRO?” Tell your healthcare provider about all your medical conditions, including if you:
• have tendon problems
• have a disease that causes muscle weakness (myasthenia gravis) have central nervous
system problems (such as epilepsy)
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• have nerve problems
• have or anyone in your family has an irregular heartbeat, especially a condition called “QT
prolongation”
• have a history of seizures
• have kidney problems. You may need a lower dose of CIPRO if your kidneys do not work
well.
• have rheumatoid arthritis (RA) or other history of joint problems
• have trouble swallowing pills
• are pregnant or planning to become pregnant. It is not known if CIPRO will harm your
unborn child.
• are breast-feeding or planning to breast-feed. CIPRO passes into breast milk. You and your
healthcare provider should decide whether you will take CIPRO or breast-feed.
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins and herbal and dietary supplements. CIPRO and other
medicines can affect each other causing side effects. Especially tell your healthcare provider if
you take:
• an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief
are NSAIDs. Taking an NSAID while you take CIPRO or other fluoroquinolones may
increase your risk of central nervous system effects and seizures. See "What are the
possible side effects of CIPRO?"
• a blood thinner (warfarin, Coumadin®, Jantoven®)
• tizanidine (Zanaflex®). You should not take CIPRO if you are already taking tizanidine.
See “Who should not take CIPRO?”
• theophylline (Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®)
• glyburide (Micronase®, Glynase®, Diabeta®, Glucovance®). See “What are the possible
side effects of CIPRO?”
• phenytoin (Fosphenytoin Sodium®, Cerebyx®, Dilantin-125®, Dilantin®, Extended
Phenytoin Sodium®, Prompt Penytoin Sodium®, Phenytek®)
• products that contain caffeine
• a medicine to control your heart rate or rhythm (antiarrhythmics) See “What are the
possible side effects of CIPRO?”
• an anti-psychotic medicine
• a tricyclic antidepressant
• a water pill (diuretic)
• a steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance
of tendon injury. See “What is the most important information I should know about
CIPRO?”
• methotrexate (Trexall®)
• Probenecid (Probalan®, Col-probenecid®)
• Metoclopromide (Reglan®, Reglan ODT®)
• Certain medicines may keep CIPRO Tablets, CIPRO Oral Suspension from working
correctly. Take CIPRO Tablets and Oral Suspension either 2 hours before or 6 hours after
taking these products:
• an antacid, multivitamin, or other product that has magnesium, calcium, aluminum, iron,
or zinc
• sucralfate (Carafate®)
• didanosine (Videx®, Videx EC®)
Ask your healthcare provider if you are not sure if any of your medicines are
listed above.
KNOW THE MEDICINES YOU TAKE. KEEP A LIST OF YOUR MEDICINES AND SHOW IT TO YOUR
HEALTHCARE PROVIDER AND PHARMACIST WHEN YOU GET A NEW MEDICINE.
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How should I take CIPRO?
• Take CIPRO exactly as prescribed by your healthcare provider.
• Take CIPRO Tablets in the morning and evening at about the same time each day. Swallow
the tablet whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you
can not swallow the tablet whole.
• Take CIPRO Oral Suspension in the morning and evening at about the same time each day.
Shake the CIPRO Oral Suspension bottle well each time before use for about 15 seconds to
make sure the suspension is mixed well. Close the bottle completely after use.
• Take CIPRO XR one time each day at about the same time each day. Swallow the tablet
whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you can not
swallow the tablet whole.
• CIPRO I.V. is given to you by intravenous (I.V.) infusion into your vein, slowly, over 60
minutes, as prescribed by your healthcare provider.
• CIPRO can be taken with or without food.
• CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices
alone, but may be taken with a meal that contains these products.
• Drink plenty of fluids while taking CIPRO.
• Do not skip any doses, or stop taking CIPRO even if you begin to feel better, until you finish
your prescribed treatment, unless:
•
you have tendon effects (see “What is the most important information I should
know about CIPRO?”),
•
you have a serious allergic reaction (see “What are the possible side effects of
CIPRO?”), or
•
your healthcare provider tells you to stop. This will help make sure that all of the bacteria are killed and lower the chance that the bacteria will become resistant to CIPRO. If this happens, CIPRO and other antibiotic medicines may not work in the future. • If you miss a dose of CIPRO Tablets or Oral Suspension, take it as soon as you remember.
Do not take two doses at the same time, and do not take more than two doses in one day.
• If you miss a dose of CIPRO XR, take it as soon as you remember. Do not take more than
one dose in one day.
• If you take too much, call your healthcare provider or get medical help immediately.
If you have been prescribed CIPRO Tablets, CIPRO Oral Suspension or CIPRO I.V.
after being exposed to anthrax:
• CIPRO Tablets, Oral Suspension and I.V. has been approved to lessen the chance
of getting anthrax disease or worsening of the disease after you are exposed to the
anthrax bacteria germ.
• Take CIPRO exactly as prescribed by your healthcare provider. Do not stop taking
CIPRO without talking with your healthcare provider. If you stop taking CIPRO too
soon, it may not keep you from getting the anthrax disease.
• Side effects may happen while you are taking CIPRO Tablets, Oral Suspension or
I.V. When taking your CIPRO to prevent anthrax infection, you and your healthcare
provider should talk about whether the risks of stopping CIPRO too soon are more
important than the risks of side effects with CIPRO.
• If you are pregnant, or plan to become pregnant while taking CIPRO, you and your
healthcare provider should decide whether the benefits of taking CIPRO Tablets, Oral
Suspension or I.V. for anthrax are more important than the risks.
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What should I avoid while taking CIPRO?
• CIPRO can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do
other activities that require mental alertness or coordination until you know how CIPRO
affects you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun. CIPRO can make
your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning
beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these
symptoms while taking CIPRO, call your healthcare provider right away. You should use a
sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight.
What are the possible side effects of CIPRO?
• CIPRO can cause side effects that may be serious or even cause death. See “What is the
most important information I should know about CIPRO?”
OTHER SERIOUS SIDE EFFECTS OF CIPRO INCLUDE:
• Central Nervous System effects
Seizures have been reported in people who take fluoroquinolone antibiotics
including CIPRO. Tell your healthcare provider if you have a history of seizures. Ask
your healthcare provider whether taking CIPRO will change your risk of having a
seizure.
CENTRAL NERVOUS SYSTEM (CNS) SIDE EFFECTS MAY HAPPEN AS SOON AS AFTER TAKING THE
FIRST DOSE OF CIPRO. TALK TO YOUR HEALTHCARE PROVIDER RIGHT AWAY IF YOU GET ANY OF
THESE SIDE EFFECTS, OR OTHER CHANGES IN MOOD OR BEHAVIOR:
• feel dizzy
• seizures
• hear voices, see things, or sense things that are not there (hallucinations)
• feel restless
• tremors
• feel anxious or nervous
• confusion
• depression
• trouble sleeping
• nightmares
• feel more suspicious (paranoia)
• suicidal thoughts or acts
• Serious allergic reactions
Allergic reactions can happen in people taking fluoroquinolones, including CIPRO, even
after only one dose. Stop taking CIPRO and get emergency medical help right away if you
get any of the following symptoms of a severe allergic reaction:
• hives
• trouble breathing or swallowing
• swelling of the lips, tongue, face
• throat tightness, hoarseness
• rapid heartbeat
• faint
• yellowing of the skin or eyes. Stop taking CIPRO and tell your healthcare provider right
away if you get yellowing of your skin or white part of your eyes, or if you have dark
urine. These can be signs of a serious reaction to CIPRO (a liver problem).
• Skin rash
Skin rash may happen in people taking CIPRO even after only one dose. Stop taking
CIPRO at the first sign of a skin rash and call your healthcare provider. Skin rash may be a
sign of a more serious reaction to CIPRO.
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•
Serious heart rhythm changes (QT prolongation and torsade de pointes)
Tell your healthcare provider right away if you have a change in your heart beat (a fast or
irregular heartbeat), or if you faint. CIPRO may cause a rare heart problem known as
prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be
very dangerous. The chances of this event are higher in people:
• who are elderly
• with a family history of prolonged QT interval
• with low blood potassium (hypokalemia)
• who take certain medicines to control heart rhythm (antiarrhythmics)
• Intestine infection (Pseudomembranous colitis)
Pseudomembranous colitis can happen with most antibiotics, including CIPRO. Call your
healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or
bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can
happen 2 or more months after you have finished your antibiotic.
• Changes in sensation and possible nerve damage (Peripheral Neuropathy)
Damage to the nerves in arms, hands, legs, or feet can happen in people who take
fluoroquinolones, including CIPRO. Talk with your healthcare provider right away if you get
any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:
• pain
• burning
• tingling
• numbness
• weakness CIPRO MAY NEED TO BE STOPPED TO PREVENT PERMANENT NERVE DAMAGE.
• Low blood sugar (hypoglycemia)
People who take CIPRO and other fluoroquinolone medicines with the oral anti-diabetes
medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar
(hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get
low blood sugar with CIPRO. Your antibiotic medicine may need to be changed.
• Sensitivity to sunlight (photosensitivity)
See “What should I avoid while taking CIPRO?”
• Joint Problems
Increased chance of problems with joints and tissues around joints in children under 18
years old. Tell your child’s healthcare provider if your child has any joint problems during or
after treatment with CIPRO.
THE MOST COMMON SIDE EFFECTS OF CIPRO INCLUDE:
• nausea
• headache
• diarrhea
• vomiting
• vaginal yeast infection
• changes in liver function tests
• pain or discomfort in the abdomen
THESE ARE NOT ALL THE POSSIBLE SIDE EFFECTS OF CIPRO. TELL YOUR HEALTHCARE PROVIDER
ABOUT ANY SIDE EFFECT THAT BOTHERS YOU, OR THAT DOES NOT GO AWAY.
CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO
FDA AT 1-800-FDA-1088.
How should I store CIPRO?
• CIPRO Tablets
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• Store CIPRO below 86°F (30°C)
• CIPRO Oral Suspension
• Store CIPRO Oral Suspension below 86°F (30°C) for up to 14 days
• Do not freeze
• After treatment has been completed, any unused oral suspension should be safely
thrown away
• CIPRO XR
• Store CIPRO XR at 59°F to 86°F (15°C to 30°C )
KEEP CIPRO AND ALL MEDICINES OUT OF THE REACH OF CHILDREN.
General Information about CIPRO
MEDICINES ARE SOMETIMES PRESCRIBED FOR PURPOSES OTHER THAN THOSE LISTED IN A
MEDICATION GUIDE. DO NOT USE CIPRO FOR A CONDITION FOR WHICH IT IS NOT PRESCRIBED. DO
NOT GIVE CIPRO TO OTHER PEOPLE, EVEN IF THEY HAVE THE SAME SYMPTOMS THAT YOU HAVE. IT
MAY HARM THEM.
THIS MEDICATION GUIDE SUMMARIZES THE MOST IMPORTANT INFORMATION ABOUT CIPRO. IF YOU
WOULD LIKE MORE INFORMATION ABOUT CIPRO, TALK WITH YOUR HEALTHCARE PROVIDER. YOU CAN
ASK YOUR HEALTHCARE PROVIDER OR PHARMACIST FOR INFORMATION ABOUT CIPRO THAT IS
WRITTEN FOR HEALTHCARE PROFESSIONALS. FOR MORE INFORMATION CALL 1-888-84 BAYER (1-888­
842-2937).
What are the ingredients in CIPRO?
• CIPRO Tablets:
• Active ingredient: ciprofloxacin
• Inactive ingredients: cornstarch, microcrystalline cellulose, silicon dioxide, crospovidone,
magnesium stearate, hypromellose, titanium dioxide, and polyethylene glycol
• CIPRO Oral Suspension:
• Active ingredient: ciprofloxacin
• Inactive ingredients: The components of the suspension have the following
compositions: Microcapsulesciprofloxacin, povidone, methacrylic acid
copolymer, hypromellose, magnesium stearate, and Polysorbate 20.
Diluentmedium-chain triglycerides, sucrose, lecithin, water, and strawberry
flavor.
• CIPRO XR:
• Active ingredient: ciprofloxacin
• Inactive ingredients: crospovidone, hypromellose, magnesium stearate, polyethylene
glycol, silica colloidal anhydrous, succinic acid, and titanium dioxide.
• CIPRO I.V.:
• Active ingredient: ciprofloxacin
• Inactive ingredients: lactic acid as a solubilizing agent, hydrochloric acid for pH adjustment Revised June 2011
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured for:
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Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 CIPRO is a registered trademark of Bayer Aktiengesellschaft.
Rx Only
06/11
©2011 Bayer HealthCare Pharmaceuticals Inc.
Printed in U.S.A.
CIPRO (ciprofloxacin*) 5% and 10% Oral Suspension Made in Italy
CIPRO (ciprofloxacin HCl) Tablets Made in Germany
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