AZITHROMYCIN
-
azithromycin tablet, film coated
Lake Erie Medical DBA Quality Care Products LLC
----------
Azithromycin 500 mg
DESCRIPTIONCiprofloxacin Tablets, USP is a
synthetic broad spectrum antimicrobial agent for oral administration.
Ciprofloxacin hydrochloride, USP, a fluoroquinolone, is the monohydrochloride
monohydrate salt of
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic
acid. It is a faintly yellowish to light yellow crystalline substance with a
empirical weight of 385.8. Its molecular formula is C
17H
18FN
3O
3•HCl•H
2O and its chemical structure is
as follows: Ciprofloxacin film-coated tablets are available in 250 mg, 500 mg, and 750 mg
(ciprofloxacin equivalent) strengths. Ciprofloxacin tablets are white to
slightly yellowish. The inactive ingredients are colloidal silicon dioxide, corn
starch, hydrogenated vegetable oil, hypromellose, magnesium stearate,
microcrystalline cellulose, polyacrylate dispersion (methylacrylate and
ethylacrylate copolymer), polyethylene glycol, purified water, simethicone
emulsion, sodium starch glycolate, talc, and titanium dioxide
CLINICAL PHARMACOLOGY
AbsorptionCiprofloxacin given as an oral tablet
is rapidly and well absorbed from the gastrointestinal tract after oral
administration. The absolute bioavailability is approximately 70% with no
substantial loss by first pass metabolism. Ciprofloxacin maximum serum
concentrations and area under the curve are shown in the chart for the 250 mg to
1000 mg dose range. are 0.1, 0.2, and 0.4 mcg/mL, respectively. The serum elimination half-life in
subjects with normal renal function is approximately 4 hours. Serum
concentrations increase proportionately with doses up to 1000 mg.
A 500
mg oral dose given every 12 hours has been shown to produce an area under the
serum concentration time curve (AUC) equivalent to that produced by an
intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12
hours. A 750 mg oral dose given every 12 hours has been shown to produce an AUC
at steady-state equivalent to that produced by an intravenous infusion of 400 mg
given over 60 minutes every 8 hours. A 750 mg oral dose results in a C
max similar to that observed with a 400 mg I.V. dose. A 250 mg
oral dose given every 12 hours produces an AUC equivalent to that produced by an
infusion of 200 mg ciprofloxacin given every 12 hours.
DistributionThe binding of ciprofloxacin to
serum proteins is 20 to 40% which is not likely to be high enough to cause
significant protein binding interactions with other drugs.
After oral
administration, ciprofloxacin is widely distributed throughout the body. Tissue
concentrations often exceed serum concentrations in both men and women,
particularly in genital tissue including the prostate. Ciprofloxacin is present
in active form in the saliva, nasal and bronchial secretions, mucosa of the
sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and
prostatic secretions. Ciprofloxacin has also been detected in lung, skin, fat,
muscle, cartilage, and bone. The drug diffuses into the cerebrospinal fluid
(CSF); however, CSF concentrations are generally less than 10% of peak serum
concentrations. Low levels of the drug have been detected in the aqueous and
vitreous humors of the eye.
MetabolismFour metabolites have been identified
in human urine which together account for approximately 15% of an oral dose. The
metabolites have antimicrobial activity, but are less active than unchanged
ciprofloxacin. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2
(CYP1A2) 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).
ExcretionThe serum elimination half-life in
subjects with normal renal function is approximately 4 hours. Approximately 40
to 50% of an orally administered dose is excreted in the urine as unchanged
drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually
exceed 200 μg/mL during the first two hours and are approximately 30 μg/mL at 8
to 12 hours after dosing. The urinary excretion of ciprofloxacin is virtually
complete within 24 hours after dosing. The renal clearance of ciprofloxacin,
which is approximately 300 mL/minute, exceeds the normal glomerular filtration
rate of 120 mL/minute. Thus, active tubular secretion would seem to play a
significant role in its elimination. Co-administration of probenecid with
ciprofloxacin results in about a 50% reduction in the ciprofloxacin renal
clearance and a 50% increase in its concentration in the systemic circulation.
Although bile concentrations of ciprofloxacin are several fold higher than serum
concentrations after oral dosing, only a small amount of the dose administered
is recovered from the bile as unchanged drug. An additional 1 to 2% of the dose
is recovered from the bile in the form of metabolites. Approximately 20 to 35%
of an oral dose is recovered from the feces within 5 days after dosing. This may
arise from either biliary clearance or transintestinal elimination.
Drug-drug InteractionsWhen Ciprofloxacin Tablet
is given concomitantly with food, there is a delay in the absorption of the
drug, resulting in peak concentrations that occur closer to 2 hours after dosing
rather than 1 hour. The overall absorption of Ciprofloxacin Tablet, however, is
not substantially affected. Concurrent administration of antacids containing
magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of
ciprofloxacin by as much as 90%. (See
PRECAUTIONS.)
The
serum concentrations of ciprofloxacin and metronidazole were not altered when
these two drugs were given concomitantly.
Concomitant administration
with tizanidine is contraindicated (See
CONTRAINDICATIONS).
Concomitant administration of ciprofloxacin with theophylline decreases the
clearance of theophylline resulting in elevated serum theophylline levels and
increased risk of a patient developing CNS or other adverse reactions.
Ciprofloxacin also decreases caffeine clearance and inhibits the formation of
paraxanthine after caffeine administration. (See
WARNINGS: PRECAUTIONS.)
Special PopulationsPharmacokinetic 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
C
max 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. 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. The kinetics of ciprofloxacin in patients
with acute hepatic insufficiency, however, have not been fully
elucidated.
Information related to pharmacokinetics
in pediatric patients is approved for Bayer Pharmaceutical Corporation's
ciprofloxacin drug products. However, due to Bayer's marketing exclusivity
rights, this drug product, produced by Hikma Pharmaceuticals, is not labeled for
pediatric use, except for inhalational anthrax (post-exposure).MICROBIOLOGYCiprofloxacin has
in vitro activity against a wide range of gram-negative and
gram-positive microorganisms. 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. 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 quinolones. There is no known cross-resistance between ciprofloxacin and
other classes of antimicrobials.
In vitro resistance
to ciprofloxacin develops slowly by multiple step mutations. 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 outsert for Ciprofloxacin Tablets.
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 only)
Streptococcus pyogenesAerobic gram-negative microorganisms
Campylobacter jejuni Proteus
mirabilis
Citrobacter diversus Proteus
vulgaris
Citrobacter freundii Providencia
rettgeri
Enterobacter cloacae Providencia
stuartii
Escherichia coli Pseudomonas
aeruginosa
Haemophilus influenzae Salmonella
typhi
Haemophilus parainfluenzae Serratia marcescens
Klebsiella pneumoniae
Shigella boydii
Moraxella catarrhalis Shigella
dysenteriae
Morganella morganii Shigella
flexneri
Neisseria gonorrhoeae Shigella
sonnei
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).
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 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 only)
Aerobic gram-negative microorganisms
Acinetobacter Iwoffi Pasteurella multocida
Aeromonas hydrophila Salmonella enteritidis
Edwardsiella
tarda Vibrio cholerae
Enterobacter
aerogenes Vibrio parahaemolyticus
Klebsiella
oxytoca Vibrio vulnificus
Legionella
pneumophila Yersinia enterocolitica
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 TechniquesQuantitative 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 method
1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized
concentrations of ciprofloxacin powder. The MIC values should be interpreted
according to the following criteria:
For testing
Enterobacteriaceae, Enterococcus faecalis,
methicillin-susceptible
Staphylococcus species,
penicillin-susceptible
Streptococcus pneumoniae, Streptococcus pyogenes, and
Pseudomonas
aeruginosa
aA 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.
Standardized susceptibility test procedures require the use of
laboratory control microorganisms to control the technical aspects of the
laboratory procedures. Standard ciprofloxacin powder should provide the
following MIC values:
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 C. jejuni
ATCC 33560 tested by broth microdilution procedure using cation adjusted
Mueller Hinton broth with 2.5 to 5% lysed horse blood in a microaerophilic
environment at 36 - 37
oC for 48 hours and for 42
oC at 24 hours
2, respectively.
c N. gonorrhoeae ATCC 49226 tested
by agar dilution procedure using GC agar and 1% defined growth supplement in a
5% CO
2 environment at 35 - 37
oC
for 20 to 24 hours
3.
Diffusion TechniquesQuantitative methods that
require measurement of zone diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds. One such standardized
procedure
3 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 following criteria:
For testing
Enterobacteriaceae,
Enterococcus
faecalis, methicillin-susceptible
Staphylococcus species, penicillin-susceptible
Streptococcus pneumoniae,
Streptococcus
pyogenes, and
Pseudomonas aeruginosa
a
INDICATIONS AND USAGECiprofloxacin Tablets,
USP are indicated for the treatment of infections caused by susceptible strains
of the designated microorganisms in the conditions and patient populations
listed below. Please see
DOSAGE AND
ADMINISTRATION for specific recommendations.
Adult Patients
Urinary Tract
Infections caused by
Escherichia coli, Klebsiella
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.
Acute Uncomplicated Cystitis in females caused by
Escherichia coli or
Staphylococcus
saprophyticus.
Chronic Bacterial Prostatitis
caused by
Escherichia coli or
Proteus mirabilis.
Lower
Respiratory Tract Infections caused by
Escherichia
coli, Klebsiella 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.
Acute Sinusitis caused by
Haemophilus influenzae, penicillin-susceptible
Streptococcus pneumoniae, or
Moraxella
catarrhalis.
Skin and Skin Structure Infections
caused by
Escherichia coli, Klebsiella pneumoniae,
Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii,
Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa,
methicillin susceptible
Staphylococcus aureus,
methicillin susceptible
Staphylococcus epidermidis,
or
Streptococcus pyogenes.
Bone and Joint Infections caused by
Enterobacter cloacae, Serratia marcescens, or
Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in combination with
metronidazole) caused by
Escherichia coli, Pseudomonas
aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or
Bacteroides fragilis.
Infectious
Diarrhea caused by
Escherichia coli
(enterotoxigenic strains),
Campylobacter jejuni,
Shigella boydii†, Shigella dysenteriae, Shigella flexneri or
Shigella sonnei† when antibacterial
therapy is indicated.
Typhoid Fever (Enteric Fever)
caused by
Salmonella typhi.
NOTE: The
efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier
state has not been demonstrated.
Uncomplicated cervical
and urethral gonorrhea due to
Neisseria
gonorrhoeae.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.
5 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).
†Although treatment of infections due to this organism in this
organ system demonstrated a clinically significant outcome, efficacy was studied
in fewer than 10 patients.
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 Ciprofloxacin
Tablets 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
Ciprofloxacin Tablets and other antibacterial drugs, Ciprofloxacin Tablets
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
CONTRAINDICATIONSCiprofloxacin 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 Ciprofloxacin Tablets, 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 rotater 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. Ciprofloxacin Tablets 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.
Pregnant Women
THE SAFETY AND
EFFECTIVENESS OF CIPROFLOXACIN IN PREGNANT AND LACTATING WOMEN HAVE NOT BEEN
ESTABLISHED. (See
PRECAUTIONS: Pregnancy,
and
Nursing Mothers
subsections.)
PediatricsCiprofloxacin 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.
Central Nervous System DisordersConvulsions,
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
Interactions and
ADVERSE
REACTIONS.)
Theophylline
SERIOUS AND FATAL
REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF
CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac
arrest, seizure, status epilepticus, and respiratory failure. Although similar
serious adverse effects 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 ReactionsSerious 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. Oxygen,
intravenous steroids, and airway management, including intubation, should be
administered as 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 Ciprofloxacin Tablets, and may range in severity from mild diarrhea to
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 NeuropathyRare 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.
SyphilisCiprofloxacin has not been shown to be
effective in the treatment of syphilis. Antimicrobial agents used in high dose
for short periods of time to treat gonorrhea may mask or delay the symptoms of
incubating syphilis. All patients with gonorrhea should have a serologic test
for syphilis at the time of diagnosis. Patients treated with ciprofloxacin
should have a follow-up serologic test for syphilis after three months.
PRECAUTIONS
GeneralCrystals 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.
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.)
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 function, is advisable during prolonged
therapy.
Prescribing Ciprofloxacin Tablets 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.
Information for PatientsPatients 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 Ciprofloxacin Tablets 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 antibacterial drugs including Ciprofloxacin Tablets should only be used
to treat bacterial infections. They do not treat viral infections (e.g., the
common cold). When Ciprofloxacin Tablets are 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
Ciprofloxacin Tablets or other antibacterial drugs in the future.
- that ciprofloxacin may be taken with or without meals and to drink fluids
liberally. As with other quinolones, concurrent administration of ciprofloxacin
with magnesium/aluminum antacids, or sucralfate, Videx®
(didanosine) chewable/buffered tablets or pediatric powder, other highly
buffered drugs, or with other products containing calcium, iron or zinc should
be avoided. Ciprofloxacin may be taken two hours before or six hours after
taking these products. Ciprofloxacin should not be taken with dairy products
(like milk or yogurt) or calcium-fortified juices alone since absorption of
ciprofloxacin may be significantly reduced; however, ciprofloxacin may be taken
with a meal that contains these products.
- 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 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 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 quinolones.
- that convulsions have been reported in patients receiving 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.)
- 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 InteractionsIn a pharmacokinetic study,
systemic exposure of tizanidine (4 mg single dose) was significantly increased
(C
max 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 a prolongation
of its serum half-life.
Concurrent administration of a quinolone,
including ciprofloxacin, with multivalent cation-containing products such as
magnesium/aluminum antacids, sucralfate,Videx
®
(didanosine) chewable/buffered tablets or pediatric powder, other highly
buffered drugs, or products containing calcium, iron, or zinc may substantially
decrease its absorption, resulting in serum and urine levels considerably lower
than desired. (See
DOSAGE AND
ADMINISTRATION for concurrent administration of these agents with
ciprofloxacin.)
Histamine H
2-receptor antagonists
appear to have no significant effect on the bioavailability of
ciprofloxacin.
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, on rare occasions, resulted in severe
hypoglycemia.
Some quinolones, including ciprofloxacin, have been
associated with transient elevations in serum creatinine in patients receiving
cyclosporine 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.
Metoclopramide significantly accelerates the absorption of
oral ciprofloxacin resulting in shorter time to reach maximum plasma
concentrations. No significant effect was observed on the bioavailability of
ciprofloxacin.
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.
Carcinogenesis, Mutagenesis, Impairment of
FertilityEight
in vitro mutagenicity tests have
been conducted with ciprofloxacin, and the test results are listed
below:
Salmonella/Microsome Test (Negative)
E.
coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation
Assay (Positive)
Chinese Hamster V
79 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, 2 of the 8 tests were positive, but results of the
following 3
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/m
2).
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/m
2), as opposed to 34 weeks when animals were treated with both
UVA and vehicle. The times to development of skin tumors ranged from 16 to 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/m
2)
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 fluoroquinolones 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 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 post-marketing 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/m
2) 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/m
2) no
maternal toxicity was produced and no embryotoxicity or teratogenicity was
observed. (See
WARNINGS.)
Nursing MothersCiprofloxacin 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
events 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%
(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.)
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 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 UseGeriatric patients are at increased
risk for developing severe tendon disorders including tendon rupture when being
treated with a fluoroquinolone such as Ciprofloxacin Tablets. 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 Ciprofloxacin Tablets to
elderly patients especially those on corticosteroids. Patients should be
informed of this potential side effect and advised to discontinue Ciprofloxacin
Tablets 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 Ciprofloxacin Tablets 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).
ADVERSE REACTIONS
Adverse Reactions in Adult PatientsDuring
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% of orally 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%), and rash (1%).
Additional medically important
events that occurred in less than 1% of ciprofloxacin patients are listed
below.
BODY AS A WHOLE: headache, abdominal pain/discomfort, foot pain,
pain, pain in extremities, injection side reaction (ciprofloxacin
intravenous)
CARDIOVASCULAR: palpitation, atrial flutter, ventricular
ectopy, syncope, hypertension, angina pectoris, myocardial infarction,
cardiopulmonary arrest, cerebral thrombosis, phlebitis, tachycardia, migraine,
hypotension
CENTRAL NERVOUS SYSTEM: restlessness, dizziness,
lightheadedness, insomnia, nightmares, hallucinations, manic reaction,
irritability, tremor, ataxia, convulsive seizures, lethargy, drowsiness,
weakness, malaise, anorexia, phobia, depersonalization, depression, paresthesia,
abnormal gait, grand mal convulsion
GASTROINTESTINAL: painful oral
mucosa, oral candidiasis, dysphagia, intestinal perforation, gastrointestinal
bleeding, cholestatic jaundice, hepatitis
HEMIC/LYMPHATIC:
lymphadenopathy, petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase
increase
MUSCULOSKELETAL: arthralgia or back pain, joint stiffness,
achiness, neck or chest pain, flare up of gout
RENAL/UROGENITAL:
interstitial nephritis, nephritis, renal failure, polyuria, urinary retention,
urethral bleeding, vaginitis, acidosis, breast pain
RESPIRATORY: dyspnea,
epistaxis, laryngeal or pulmonary edema, hiccough, hemoptysis, bronchospasm,
pulmonary embolism
SKIN/HYPERSENSITIVITY: allergic reaction, pruritus,
urticaria, photosensitivity/phototoxicity reaction, flushing, fever, chills,
angioedema, edema of the face, neck, lips, conjunctivae or hands, cutaneous
candidiasis, hyperpigmentation, erythema nodosum, sweating
SPECIAL
SENSES: blurred vision, disturbed vision (change in color perception,
overbrightness of lights), decreased visual acuity, diplopia, eye pain,
tinnitus, hearing loss, bad taste, chromatopsia
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 tablets (500 mg
BID) to cefuroxime axetil (250 mg - 500 mg BID) and to clarithromycin (500 mg
BID) in patients with respiratory tract infections, ciprofloxacin demonstrated a
CNS adverse event profile comparable to 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 U.S., 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% (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.
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%,
rhinitis 3%, 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 ReportThe following
adverse events have been reported from worldwide marketing experience with
quinolones, 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, anaphylactic reactions
(including life-threatening anaphylactic shock), 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, myasthenia gravis (possible exacerbation), myoclonus,
nystagmus, pancreatitis, pancytopenia (life threatening or fatal outcome),
peripheral neuropathy, phenytoin alteration (serum),
photosensitivity/phototoxicity reaction, potassium elevation (serum),
prothrombin time prolongation or 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
Changes in laboratory parameters listed as adverse events without
regard to drug relationship are listed below:
Hepatic –
Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%), alkaline phosphatase (0.8%),
LDH (0.4%), serum bilirubin (0.3%).
Hematologic – Eosinophilia
(0.6%), leukopenia (0.4%), decreased blood platelets (0.1%), elevated blood
platelets (0.1%), pancytopenia (0.1%).
Renal – Elevations
of serum creatinine (1.1%), BUN (0.9%), CRYSTALLURIA, CYLINDRURIA, AND
HEMATURIA HAVE BEEN REPORTED.
Other changes occurring in less than 0.1%
of courses were: elevation of serum gammaglutamyl transferase, elevation of
serum amylase, reduction in blood glucose, elevated uric acid, decrease in
hemoglobin, anemia, bleeding diathesis, increase in blood monocytes,
leukocytosis.
To report SUSPECTED ADVERSE EVENTS, contact West-ward Pharmaceutical Corp. at
1-877-233-2001 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
OVERDOSAGEIn the event of acute overdosage,
reversible renal toxicity has been reported in some cases. The stomach should be
emptied by inducing vomiting or by gastric lavage. The patient should be
carefully observed and given supportive treatment, including monitoring of renal
function and administration of magnesium, aluminum, or calcium containing
antacids which can reduce the absorption of ciprofloxacin. Adequate hydration
must be maintained. Only a small amount of ciprofloxacin (less than 10%) is removed
from the body after hemodialysis or peritoneal dialysis.
Single doses of
ciprofloxacin were relatively non-toxic via the oral route of administration in
mice, rats, and dogs. No deaths occurred within a 14-day post treatment
observation period at the highest oral doses tested; up to 5000 mg/kg in either
rodent species, or up to 2500 mg/kg in the dog. Clinical signs observed included
hypoactivity and cyanosis in both rodent species and severe vomiting in dogs. In
rabbits, significant mortality was seen at doses of ciprofloxacin greater than 2500
mg/kg. Mortality was delayed in these animals, occurring 10 to 14 days after
dosing.
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
DOSAGE AND ADMINISTRATION - ADULTSCiprofloxacin
Tablets should be administered orally to adults as described in the Dosage
Guidelines table.
The determination of dosage for any particular patient
must take into consideration the severity and nature of the infection, the
susceptibility of the causative organism, the integrity of the patient’s
host-defense mechanisms, and the status of renal function and hepatic
function.
The duration of treatment depends upon the severity of
infection. The usual duration is 7 to 14 days; however, for severe and
complicated infections more prolonged therapy may be required. Ciprofloxacin
should be administered at least 2 hours before or 6 hours after
magnesium/aluminum antacids, or sucralfate, Videx
®
(didanosine) chewable/buffered tablets or pediatric powder for oral solution,
other highly buffered drugs, or other products containing calcium, iron or zincWhen only the serum creatinine concentration is known, the following formula may
be used to estimate creatinine
clearance.
Weight (kg) x (140 - age)
Men: Creatinine clearance
(mL/min) = 72 x serum creatinine (mg/dL)
Women: 0.85 x the
value calculated for men.
The serum creatinine should represent a steady
state of renal function.
In patients with severe infections and severe
renal impairment, a unit dose of 750 mg may be administered at the intervals
noted above. Patients should be carefully monitored.
DOSAGE AND ADMINISTRATION -
PEDIATRICSCiprofloxacin Tablets should be administered orally 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 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 less than 50 mL/min/1.73m
2
HOW SUPPLIED
Ciprofloxacin Tablets USP, are available
as white, round, film-coated tablets containing 250 mg ciprofloxacin. The 250 mg
tablet is coded with "WW927" on one side.
Ciprofloxacin Tablets, USP area also available as white, capsule shaped,
film-coated tablets containing 500 mg or 750 mg ciprofloxacin. The 500 mg tablet
is coded with "WW928" on one side. The 750 mg tablet is coded with "WW929" on
one side. Ciprofloxacin Tablets, USP 250 mg and 500 mg are available in bottles
of 30's, 100's and 500's.
Ciprofloxacin Tablets, USP 750 mg are available in bottles of 50's and 100's
and Unit Dose Boxes of 100 tablets.
Strength Tablet Identification
Bottles of 30's: 250
mg WW927
500
mg WW928
Bottles of
50's: 750
mg WW929
Bottles of
100's: 250
mg WW927
500
mg WW928
750
mg WW929
Bottles of
500's: 250
mg WW927
500
mg WW928
Unit Dose Boxes of
100 250
mg WW927
500
mg WW928
750
mg WW929
Store at 20-25°C (68-77°F) [See USP Controlled Room
Temperature]. Dispense in a well-closed container as defined in the USP using a
child-resistant closure.
Information for PatientsPatients 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 Ciprofloxacin Tablets 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 antibacterial drugs including Ciprofloxacin Tablets should only be used
to treat bacterial infections. They do not treat viral infections (e.g., the
common cold). When Ciprofloxacin Tablets are 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
Ciprofloxacin Tablets or other antibacterial drugs in the future.
- that ciprofloxacin may be taken with or without meals and to drink fluids
liberally. As with other quinolones, concurrent administration of ciprofloxacin
with magnesium/aluminum antacids, or sucralfate, Videx®
(didanosine) chewable/buffered tablets or pediatric powder, other highly
buffered drugs, or with other products containing calcium, iron or zinc should
be avoided. Ciprofloxacin may be taken two hours before or six hours after
taking these products. Ciprofloxacin should not be taken with dairy products
(like milk or yogurt) or calcium-fortified juices alone since absorption of
ciprofloxacin may be significantly reduced; however, ciprofloxacin may be taken
with a meal that contains these products.
- 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 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 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 quinolones.
- that convulsions have been reported in patients receiving 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.)
- 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 InteractionsIn a pharmacokinetic study,
systemic exposure of tizanidine (4 mg single dose) was significantly increased
(C
max 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 a prolongation
of its serum half-life.
Concurrent administration of a quinolone,
including ciprofloxacin, with multivalent cation-containing products such as
magnesium/aluminum antacids, sucralfate,Videx
®
(didanosine) chewable/buffered tablets or pediatric powder, other highly
buffered drugs, or products containing calcium, iron, or zinc may substantially
decrease its absorption, resulting in serum and urine levels considerably lower
than desired. (See
DOSAGE AND
ADMINISTRATION for concurrent administration of these agents with
ciprofloxacin.)
Histamine H
2-receptor antagonists
appear to have no significant effect on the bioavailability of
ciprofloxacin.
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, on rare occasions, resulted in severe
hypoglycemia.
Some quinolones, including ciprofloxacin, have been
associated with transient elevations in serum creatinine in patients receiving
cyclosporine 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.
Metoclopramide significantly accelerates the absorption of
oral ciprofloxacin resulting in shorter time to reach maximum plasma
concentrations. No significant effect was observed on the bioavailability of
ciprofloxacin.
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.
Carcinogenesis, Mutagenesis, Impairment of
FertilityEight
in vitro mutagenicity tests have
been conducted with ciprofloxacin, and the test results are listed
below:
Salmonella/Microsome Test (Negative)
E.
coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation
Assay (Positive)
Chinese Hamster V
79 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, 2 of the 8 tests were positive, but results of the
following 3
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/m
2).
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/m
2), as opposed to 34 weeks when animals were treated with both
UVA and vehicle. The times to development of skin tumors ranged from 16 to 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/m
2)
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 fluoroquinolones 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 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 post-marketing 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/m
2) 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/m
2) no
maternal toxicity was produced and no embryotoxicity or teratogenicity was
observed. (See
WARNINGS.)
Nursing MothersCiprofloxacin 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
events 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%
(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.)
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 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 UseGeriatric patients are at increased
risk for developing severe tendon disorders including tendon rupture when being
treated with a fluoroquinolone such as Ciprofloxacin Tablets. 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 Ciprofloxacin Tablets to
elderly patients especially those on corticosteroids. Patients should be
informed of this potential side effect and advised to discontinue Ciprofloxacin
Tablets 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 Ciprofloxacin Tablets 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).
WARNING
Fluoroquinolones, including
Ciprofloxacin Tablets, 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).
CIPROFLOXACIN - ciprofloxacin tablet, film
coated
West-ward Pharmaceutical Corp
----------
MEDICATION GUIDE
Ciprofloxacin Tablets,
USP
Read the Medication Guide that comes with Ciprofloxacin
Tablets 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 Ciprofloxacin
Tablets?Ciprofloxacin Tablets belong to a class of antibiotics called
fluoroquinolones. Ciprofloxacin Tablets 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 Ciprofloxacin Tablets.
Tendon rupture or swelling of the tendon (tendinitis)
- Tendons are tough cords of tissue that connect muscles to bones.
- Pain, swelling, tears, and inflammation of tendons including the back of the
ankle (Achilles), shoulder, hand, or other tendon sites can happen in people of
all ages who take fluoroquinolone antibiotics, including Ciprofloxacin Tablets.
The risk of getting tendon problems is higher if you:
- are over 60 years of age
- are taking steroids (corticosteroids)
- have had a kidney, heart, or lung transplant.
Swelling of the tendon
(tendinitis) and tendon rupture (breakage) have also happened in patients who
take fluoroquinolones who do not have the above risk factors.
- Other reasons for tendon ruptures 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 Ciprofloxacin Tablets 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. Talk to your healthcare provider about the risk of tendon rupture with
continued use of Ciprofloxacin Tablets. 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 Ciprofloxacin Tablets. 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
- See the section “What are the possible side
effects of Ciprofloxacin Tablets?” for more information about side
effects.
What are Ciprofloxacin Tablets?Ciprofloxacin Tablets are 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 Ciprofloxacin Tablets. Ciprofloxacin Tablets
should not be used as the first choice of antibiotic medicine in children under
18 years of age. Ciprofloxacin Tablets 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).
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
Ciprofloxacin Tablets, do not kill viruses.
Call your healthcare provider if you think your condition is not
getting better while you are taking Ciprofloxacin Tablets.
Who should not take Ciprofloxacin Tablets?
Do not take Ciprofloxacin Tablets 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 Ciprofloxacin
Tablets. Ask your healthcare provider if you are not sure. See the list of
ingredients in Ciprofloxacin Tablets 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 Ciprofloxacin
Tablets?
See “What is the most important
information I should know about Ciprofloxacin Tablets?”
Tell your healthcare provider about all your medical
conditions, including if you:
- have tendon problems
- have central nervous system problems (such as epilepsy)
- 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 Ciprofloxacin Tablets 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
ciprofloxacin tablets will harm your unborn child.
- are breast-feeding or planning to breast-feed. Ciprofloxacin passes into
breast milk. You and your healthcare provider should decide whether you will
take Ciprofloxacin Tablets 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. Ciprofloxacin Tablets 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 Ciprofloxacin Tablets or
other fluoroquinolones may increase your risk of central nervous system effects
and seizures. See “What are the possible side
effects of Ciprofloxacin Tablets?”
- a blood thinner (Warfarin, Coumadin®, Jantoven®)
- tizanidine (Zanaflex®). You should not take
Ciprofloxacin Tablets if you are already taking tizanidine. See “Who should not
take Ciprofloxacin Tablets?”
- theophylline (Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®)
- glyburide (Micronase®, Glynase®, Diabeta®, Glucovance®). See “What are the possible side
effects of Ciprofloxacin Tablets?”
- 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 Ciprofloxacin Tablets?”
- 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 ciprofloxacin tablets?”
- methotrexate (Trexall®)
- Probenecid (Probalan®, Col-probenacid®)
- Metoclopromide (Reglan®, Reglan ODT®)
- Certain medicines may keep Ciprofloxacin Tablets from working correctly.
Take Ciprofloxacin Tablets 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
- 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.
How should I take Ciprofloxacin Tablets?
- Take Ciprofloxacin Tablets exactly as prescribed by your healthcare
provider.
- Take Ciprofloxacin 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.
- Ciprofloxacin Tablets can be taken with or without food.
- Ciprofloxacin Tablets 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 Ciprofloxacin Tablets.
- Do not skip any doses, or stop taking Ciprofloxacin Tablets even if you
begin to feel better, until you finish your prescribed treatment, unless:
This will
help make sure that all of the bacteria are killed and lower the chance that the
bacteria will become resistant to Ciprofloxacin Tablets. If this happens,
ciprofloxacin tablets and other antibiotic medicines may not work in the future.
- If you miss a dose of Ciprofloxacin Tablets, 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 take too much, call your healthcare provider or get medical help
immediately.
If you have been prescribed Ciprofloxacin
Tablets after being exposed to anthrax:
- Ciprofloxacin Tablets have 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 Ciprofloxacin Tablets exactly as prescribed by your healthcare
provider. Do not stop taking Ciprofloxacin Tablets without talking with your
healthcare provider. If you stop taking ciprofloxacin tablets too soon, it may
not keep you from getting the anthrax disease.
- Side effects may happen while you are taking Ciprofloxacin Tablets. When
taking your Ciprofloxacin Tablets to prevent anthrax infection, you and your
healthcare provider should talk about whether the risks of stopping
Ciprofloxacin Tablets too soon are more important than the risks of side effects
with Ciprofloxacin Tablets.
- If you are pregnant, or plan to become pregnant while taking Ciprofloxacin
Tablets, you and your healthcare provider should decide whether the benefits of
taking Ciprofloxacin Tablets for anthrax are more important than the risks.
What should I avoid while taking Ciprofloxacin Tablets?
- Ciprofloxacin Tablets 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 Ciprofloxacin Tablets affect you.
- Avoid sunlamps, tanning beds, and try to limit your time in the sun.
Ciprofloxacin Tablets 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
Ciprofloxacin Tablets, 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 Ciprofloxacin Tablets?
Other serious side effects of Ciprofloxacin Tablets include:
-
Central Nervous System Effects
Seizures have been reported in people who take fluoroquinolone antibiotics
including Ciprofloxacin Tablets. Tell your healthcare provider if you have a
history of seizures. Ask your healthcare provider whether taking Ciprofloxacin
Tablets 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 Ciprofloxacin Tablets. 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 Ciprofloxacin Tablets, even
after only one dose. Stop taking Ciprofloxacin Tablets 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 Ciprofloxacin Tablets 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 Ciprofloxacin Tablets (a liver problem).
Skin rash may happen in people taking ciprofloxacin tablets even after only
one dose. Stop taking ciprofloxacin tablets 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 ciprofloxacin tablets.
-
Serious heart rhythm changes (QT prolongation and
torsades 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. Ciprofloxacin Tablets 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
Ciprofloxacin Tablets. 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 Ciprofloxacin Tablets. 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
Ciprofloxacin Tablets may need to be stopped to prevent permanent nerve
damage.
-
Low blood sugar (hypoglycemia)
People who take Ciprofloxacin Tablets 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 Ciprofloxacin
Tablets. Your antibiotic medicine may need to be changed.
-
Sensitivity to sunlight (photosensitivity)
See “What should I avoid while
taking Ciprofloxacin Tablets?”
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 Ciprofloxacin Tablets.
The most common side effects of Ciprofloxacin Tablets 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 Ciprofloxacin Tablets. 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 Ciprofloxacin Tablets?
Store
at 20-25°C (68-77°F) [See USP Controlled Room Temperature].
Keep Ciprofloxacin Tablets and all medicines out of the reach of
children.General Information about Ciprofloxacin Tablets
Medicines are sometimes prescribed for purposes other than those
listed in a Medication Guide. Do not use Ciprofloxacin Tablets for a condition
for which it is not prescribed. Do not give Ciprofloxacin Tablets to other
people, even if they have the same symptoms that you have. They may harm them.
This Medication Guide summarizes the most important information about
Ciprofloxacin Tablets. If you would like more information about Ciprofloxacin
Tablets, talk with your healthcare provider. You can ask your healthcare
provider or pharmacist for information about Ciprofloxacin Tablets that is
written for healthcare professionals. For more information call 1-866-850-2876.
What are the ingredients in Ciprofloxacin Tablets?
Active ingredient: ciprofloxacin
Inactive ingredients: colloidal silicon dioxide, corn starch, hydrogenated
vegetable oil, hypromellose, magnesium stearate, microcrystalline cellulose,
polyacrylate dispersion (methylacrylate and ethylacrylate copolymer),
polyethylene glycol, purified water, simethicone emulsion, sodium starch
glycolate, talc, and titanium dioxide.
Revised March 2009
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
West-ward Pharmaceutical
Corp.
Eatontown, NJ 07724
Distributor
Manufactured by:
Hikma Pharmaceuticals
P.O. Box
182400
Amman 11118 - Jordan
Revised: 06/2010West-ward
Pharmaceutical Corp
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AZITHROMYCIN
azithromycin
tablet, film coated |
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Revised: 11/2010Lake Erie Medical DBA Quality Care Products LLC