Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2550
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Ciprofloxacin (Injection, Solution, Concentrate)
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Ciprofloxacin Injection, USP is a synthetic broad-spectrum
antimicrobial agent for intravenous (I.V.) administration. Ciprofloxacin,
a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic
acid. Its empirical formula is CHFNOand its chemical structure is: Ciprofloxacin is a faint to light yellow crystalline
powder with a molecular weight of 331.4. It is soluble in dilute (0.1N)
hydrochloric acid and is practically insoluble in water and ethanol.
Ciprofloxacin Injection, USP is available as a sterile 1% aqueous
concentrate, which is intended for dilution prior to administration.
The formula contains lactic acid as a solubilizing agent and hydrochloric
acid for pH adjustment. The pH range for the 1% aqueous concentrate
in vials is 3.3 to3.9.
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Absorption Following 60-minute intravenous infusions of 200 mg and
400 mg ciprofloxacin to normal volunteers, the mean maximum serum
concentrations achieved were 2.1 and 4.6 mcg/mL, respectively; the
concentrations at 12 hours were 0.1 and 0.2 mcg/mL, respectively. The pharmacokinetics of ciprofloxacin are linear
over the dose range of 200 to 400 mg administered intravenously. Comparison
of the pharmacokinetic parameters following the 1st and 5th I.V. dose
on a q 12 h regimen indicates no evidence of drug accumulation. The absolute bioavailability of oral ciprofloxacin is
within a range of 70 to 80% with no substantial loss by first pass
metabolism. An intravenous infusion of 400 mg ciprofloxacin given
over 60 minutes every 12 hours has been shown to produce an area under
the serum concentration time curve (AUC) equivalent to that produced
by a 500 mg oral dose given every 12 hours. An intravenous infusion
of 400 mg ciprofloxacin given over 60 minutes every 8 hours has been
shown to produce an AUC at steady-state equivalent to that produced
by a 750 mg oral dose given every 12 hours. A 400 mg I.V. dose results
in a Csimilar to that observed with a 750 mg oral dose.
An infusion of 200 mg ciprofloxacin given every 12 hours produces
an AUC equivalent to that produced by a 250 mg oral dose given every
12 hours. Distribution After intravenous administration, ciprofloxacin
is present in saliva, nasal and bronchial secretions, sputum, skin
blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions.
It has also been detected in the lung, skin, fat, muscle, cartilage,
and bone. Although the drug diffuses into cerebrospinal fluid (CSF),
CSF concentrations are generally less than 10% of peak serum concentrations.
Levels of the drug in the aqueous and vitreous chambers of the eye
are lower than in serum. Metabolism After I.V. administration,
three metabolites of ciprofloxacin have been identified in human urine
which together account for approximately 10% of the intravenous dose.
The binding of ciprofloxacin to serum proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human cytochrome P450
1A2 (CYP1A2) 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, and PRECAUTIONS: Drug Interactions.) Excretion The serum
elimination half-life is approximately 5 to 6 hours and the total
clearance is around 35 L/hr. After intravenous administration, approximately
50% to 70% of the dose is excreted in the urine as unchanged drug.
Following a 200 mg I.V. dose, concentrations in the urine usually
exceed 200 mcg/mL 0 to 2 hours after dosing and are generallygreater
than 15 mcg/mL 8 to 12 hours after dosing. Following a 400 mg I.V.
dose, urine concentrations generally exceed 400 mcg/mL 0 to 2 hours
after dosing and are usually greater than 30 mcg/mL 8 to 12 hours
after dosing. The renal clearance is approximately 22 L/hr. The urinary
excretion of ciprofloxacin is virtually complete by 24 hours after
dosing. Although bile concentrations of ciprofloxacin
are several fold higher than serum concentrations after intravenous
dosing, only a small amount of the administered dose (<1%) is
recovered from the bile as unchanged drug. Approximately 15% of an
I.V. dose is recovered from the feces within 5 days after dosing. Special Populations Pharmacokinetic studies of the oral (single
dose) and intravenous (single and multiple dose) forms of ciprofloxacin
indicate that plasma concentrations of ciprofloxacin are higher in
elderly subjects (>65 years) as compared to young adults. Although
the Cis increased 16 to 40%, the increase in mean AUC
is approximately 30%, and can be at least partially attributed to
decreased renal clearance in the elderly. Elimination half-life is
only slightly (~20%) prolonged in the elderly. These differences are
not considered clinically significant. (See PRECAUTIONS: Geriatric Use.) In patients with
reduced renal function, the half-life of ciprofloxacin is slightly
prolonged and dosage adjustments may be required. (See DOSAGE AND ADMINISTRATION.) In preliminary studies in patients with stable chronic
liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics
have been observed. However, the kinetics of ciprofloxacin in patients
with acute hepatic insufficiency have not been fully elucidated. 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 Hospira, Inc., is not labeled
for pediatric use, except for inhalational anthrax (post-exposure). Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated. (See CONTRAINDICATIONS.) The potential
for pharmacokinetic drug interactions between ciprofloxacin and theophylline,
caffeine, cyclosporins, phenytoin, sulfonylurea glyburide, metronidazole,
warfarin, probenecid, and piperacillin sodium has been evaluated.
(See WARNINGS and PRECAUTIONS: Drug Interactions.) Microbiology Ciprofloxacin 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
I.V., which are required for bacterial DNA replication, transcription,
repair, and recombination. The mechanism of action of fluoroquinolones,
including ciprofloxacin, is different fromthat 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 insert for Ciprofloxacin
Injection, USP. 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 mcg/mL or less against most (���90%)
strains of the following microorganisms; however, the safety and effectiveness
of ciprofloxacin intravenous formulations in treating clinical infections
due to these microorganisms have not been established in adequate
and well-controlled clinical trials. Most strains of Burkholderia
cepacia and some strains of Stenotrophomonas maltophilia are resistant to ciprofloxacin
as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium
difficile. Susceptibility Tests Dilution Techniques: Quantitative methods
are used to determine antimicrobial minimum inhibitory concentrations
(MICs). These MICs provide estimates of the susceptibility of bacteria
to antimicrobial compounds. The MICs should be determined using a
standardized procedure. Standardized procedures are based on a dilution
method(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: These interpretive standards are applicable
only to broth microdilution susceptibility tests with streptococci
using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse
blood. For testing Haemophilus influenzae and Haemophilus parainfluenzae: This interpretive standard is applicable
only to broth microdilution susceptibility tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium.
The current absence of data on resistant strains precludes defining
any results other than���Susceptible���. Strains yielding
MIC results suggestive of a���nonsusceptible���category
should be submitted to a reference laboratory for further testing. A report of���Susceptible���indicates that
the pathogen is likely to be inhibited if the antimicrobial compound
in the blood reaches the concentrations usually achievable. A report
of���Intermediate���indicates that the result should be
considered equivocal, and, if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated.
This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where
high dosage of drug can be used. This category also provides a buffer
zone, which prevents small uncontrolled technical factors from causing
major discrepancies in interpretation. A report of���Resistant���indicates that the pathogen is not likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable;
other therapy should be selected. 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). Diffusion Techniques: Quantitative methods that require measurement of zone diameters also
provide reproducible estimates of the susceptibility of bacteria to
antimicrobial compounds. One such standardized procedurerequires the use of standardized inoculum concentrations. This procedure
uses paper disks impregnated with 5-mcg 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-mcg 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: These zone diameter standards are
applicable only to tests performed for streptococci using Mueller-Hinton
agar supplemented with 5% sheep blood incubated in 5% CO. For testing Haemophilus influenzae and Haemophilus parainfluenzae: This zone diameter standard is applicable
only to tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium
(HTM). The current absence of data
on resistant strains precludes defining any results other than���Susceptible���.
Strains yielding zone diameter results suggestive of a���nonsusceptible���category should be submitted to a reference laboratory for further
testing. Interpretation should be as stated
above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC
for ciprofloxacin. As with standardized dilution
techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the
laboratory procedures. For the diffusion technique, the 5-mcg ciprofloxacin
disk should provide the following zone diameters in these laboratory
test quality control strains: These quality control limits are applicable
to only H. influenzae ATCC
49247 testing using Haemophilus Test Medium (HTM).
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Ciprofloxacin is contraindicated in persons with
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.)
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Ciprofloxacin Injection, USP is available as a clear,
colorless to slightly yellowish solution. Ciprofloxacin Injection,
USP is available in 200 mg and 400 mg strengths. The concentrate is
supplied in vials as follows: VIAL: manufactured by Hospira, Inc., Lake
Forest, IL 60045. STORAGE Store at 20 to 25��C (68 to 77��F).
[See USP Controlled Room Temperature.] Protect
from light, protect from freezing.
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General:: INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED
BY SLOW INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions
have been reported with the intravenous administration of ciprofloxacin.
These reactions are more frequent if infusion time is 30 minutes or
less or if small veins of the hand are used. (See ADVERSE REACTIONS.) Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous
system (CNS) events, including: nervousness, agitation, insomnia,
anxiety, nightmares or paranoia. (See PRECAUTIONS: Information for
Patients and Drug Interactions.) Crystals of ciprofloxacin have been observed
rarely in the urine of human subjects but more frequently in the urineof laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.) Crystalluria
related to ciprofloxacin has been reported only rarely in humans because
human urine is usually acidic. Alkalinity of the urine should be avoided
in patients receiving ciprofloxacin. Patients should be well hydrated
to prevent the formation of highly concentrated urine. Renal Impairment: Alteration of the dosage regimen is necessary for patients with impairment
of renal function. (See DOSAGE AND
ADMINISTRATION.) Phototoxicity: Moderate to severe phototoxicity
manifested as an exaggerated sunburn reaction has been observed in
some patients who were exposed to direct sunlight while receiving
some members of the quinolone class of drugs. Excessive sunlight should
be avoided. As with any potent drug, periodic
assessment of organ system functions, including renal, hepatic, and
hematopoietic, is advisable during prolonged therapy. Prescribing Ciprofloxacin Injection, USP in the absence of a proven
or strongly suspected bacterial infection or a prophylactic indication
is unlikely to provide benefit to the patient and increase the risk
of the development of drug-resistant bacteria.<br/>Information For Patients:: Patients should be advised:<br/>Drug Interactions:: In a pharmacokinetic study, systemic exposure of
tizanidine (4 mg single dose) was significantly increased (C7-fold, AUC 10-fold) when the drug was given concomitantly with
ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative
effects of tizanidine were also potentiated. Concomitant administration
of tizanidine and ciprofloxacin is contraindicated. As with some other quinolones, concurrent administration of ciprofloxacin
with theophylline may lead to elevated serum concentrations of theophylline
and prolongation of its elimination half-life. This may result in
increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant use cannot
be avoided, serum levels of theophylline should be monitored and dosage
adjustments made as appropriate. Some quinolones,
including ciprofloxacin, have also been shown to interfere with the
metabolism of caffeine. This may lead to reduced clearance of caffeine
and prolongation of its serum half-life. Some
quinolones, including ciprofloxacin, have been associated with transient
elevations in serum creatinine in patients receiving cyclosporine
concomitantly. Altered serum levels of phenytoin
(increased and decreased) have been reported in patients receiving
concomitant ciprofloxacin. The concomitant administration
of ciprofloxacin with the sulfonylurea glyburide has, in some patients,
resulted in severe hypoglycemia. Fatalities have been reported. The serum concentrations of ciprofloxacin and metronidazole
were not altered when these two drugs were given concomitantly. Quinolones, including ciprofloxacin, have been reported
to enhance the effects of the oral anticoagulant warfarin or its derivatives.
When these products are administered concomitantly, prothrombin time
or other suitable coagulation tests should be closely monitored. Probenecid interferes with renal tubular secretion of
ciprofloxacin and produces an increase in the level of ciprofloxacin
in the serum. This should be considered if patients are receiving
both drugs concomitantly. Renal tubular transport
of methotrexate may be inhibited by concomitant administration of
ciprofloxacin potentially leading to increased plasma levels of methotrexate.
This might increase the risk of methotrexate associated toxic reactions.
Therefore, patients under methotrexate therapy should be carefully
monitored when concomitant ciprofloxacin therapy is indicated. Non-steroidal anti-inflammatory drugs (but not acetyl
salicylic acid) in combination of very high doses of quinolones have
been shown to provoke convulsions in pre-clinical studies. Following infusion of 400 mg I.V. ciprofloxacin every
eight hours in combination with 50 mg/kg I.V. piperacillin sodium
every four hours, mean serum ciprofloxacin concentrations were 3.02
mcg/mL 0.5 hour and 1.18 mcg/mL between 6 to 8 hours after the end
of infusion.<br/>Carcinogenesis, Mutagenesis,
Impairment of Fertility:: Eight in vitro mutagenicity tests have been conducted with ciprofloxacin. Test results
are listed below: Salmonella/Microsome Test
(Negative) E. coli DNA Repair Assay (Negative) Mouse Lymphoma
Cell Forward Mutation Assay (Positive) Chinese
Hamster VCell HGPRT Test (Negative) Syrian Hamster Embryo Cell Transformation Assay (Negative) Saccharomyces cerevisiae Point Mutation Assay (Negative) Saccharomyces cerevisiae Mitotic Crossover
and Gene Conversion Assay (Negative) Rat Hepatocyte DNA Repair Assay (Positive) Thus, two of the eight tests were positive, but results
of the following three in vivo test systems gave negative results: Rat Hepatocyte
DNA Repair Assay Micronucleus Test (Mice) Dominant Lethal Test (Mice) Long-term
carcinogenicity studies in rats and mice resulted in no carcinogenic
or tumorigenic effects due to ciprofloxacin at daily oral dose levels
up to 250 and 750 mg/kg to rats and mice, respectively (approximately
1.7 and 2.5 times the highest recommended therapeutic dose based upon
mg/m). 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), 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. 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) revealed no evidence of impairment.<br/>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. A controlled
prospective observational study followed 200 women exposed to fluoroquinolones
(52.5% exposed to ciprofloxacin and 68% first trimester exposures)
during gestation.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 to 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).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.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 times and 1.3 times the highest
recommended therapeutic dose based upon mg/m) 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) no maternal toxicity was produced,
and no embryotoxicity or teratogenicity was observed. (See WARNINGS.)<br/>Nursing Mothers:: Ciprofloxacin is excreted in human milk. The amount
of ciprofloxacin absorbed by the nursing infant is unknown. Because
of the potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, a decision should be made whether
to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother.<br/>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 the 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 Information
related to the safety and efficacy of ciprofloxacin in pediatric patients
for the treatment of complicated urinary tract infections and pyelonephritis
is approved for Bayer Pharmaceutical Corporation's ciprofloxacin
drug products. 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. The rates of these events in pediatric patients with complicated
urinary tract infection and pyelonephritis within six weeks of follow-up
were 9.3% (31/335) versus 6.0% (21/349) for control agents. The rates
of these events occurring at any time up to the one year follow-up
were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all
adverse events regardless of drug relationship at six weeks was 41%
(138/335) in the ciprofloxacin arm compared to 31% (109/349) in the
control arm. (See ADVERSE REACTIONS.) Due to Bayer's marketing exclusivity rights, this drug product,
produced by Hospira, Inc., is not labeled for pediatric use, except
for inhalational anthrax (post-exposure). 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 to 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 to 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 to 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 to 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 the
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 and11% 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 cannot be definitively determined, particularly
since patients with cystic fibrosis may develop arthralgias/arthritis
as part of their underlying disease process.<br/>Geriatric Use:: 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 knownto
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.)
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In the event of acute overdosage, the patient should
be carefully observed and given supportive treatment, including monitoring
of renal function. Adequate hydration must be maintained. Only a small
amount of ciprofloxacin (<10%) is removed from the body after hemodialysis
or peritoneal dialysis. In mice, rats, rabbits
and dogs, significant toxicity including tonic/clonic convulsions
was observed at intravenous doses of ciprofloxacin between 125 and
300 mg/kg.
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Ciprofloxacin
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Ciprofloxacin (Injection, Solution, Concentrate)
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Adverse Reactions in Adult
Patients: During clinical investigations with oral and parenteral
ciprofloxacin, 49,038 patients received courses of the drug. Most
of the adverse events reported were described as only mild or moderate
in severity, abated soon after the drug was discontinued, and required
no treatment. Ciprofloxacin was discontinued because of an adverse
event in 1.8% of intravenously treated patients. The most frequently reported drug related events, from clinical trials
of all formulations, all dosages, all drug-therapy durations, and
for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea
(1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and
rash (1.0%). In clinical trials the following
events were reported, regardless of drug relationship, in greater
than 1% of patients treated with intravenous ciprofloxacin: nausea,
diarrhea, central nervous system disturbance, local I.V. site reactions,
liver function tests abnormal, eosinophilia, headache, restlessness,
and rash. Many of these events were described as only mild or moderate
in severity, abated soon after the drug was discontinued, and required
no treatment. Local I.V. site reactions are more frequent if the infusion
time is 30 minutes or less. These may appear as local skin reactions
which resolve rapidly upon completion of the infusion. Subsequent
intravenous administration is not contraindicated unless the reactions
recur or worsen. Additional medically important
events, without regard to drug relationship or route of administration,
that occurred in 1% or less of ciprofloxacin patients are listed below: BODY AS A WHOLE: abdominal pain/discomfort, foot pain,
pain, pain in extremities CARDIOVASCULAR: cardiovascular
collapse, cardiopulmonary arrest, myocardial infarction, arrhythmia,
tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur,
hypertension, hypotension, angina pectoris, atrial flutter, ventricular
ectopy, (thrombo)-phlebitis, vasodilation, migraine CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis,
depression, dysphasia, phobia, depersonalization, manic reaction,
unresponsiveness, ataxia, confusion, hallucinations, dizziness, lightheadedness,
paresthesia, anxiety, tremor, insomnia, nightmares, weakness, drowsiness,
irritability, malaise, lethargy, abnormal gait, grand mal convulsion,
anorexia GASTROINTESTINAL: ileus, jaundice,
gastrointestinal bleeding, C. difficile associated diarrhea, pseudomembranous colitis, pancreatitis, hepatic
necrosis, intestinal perforation, dyspepsia, epigastric pain, constipation,
oral ulceration, oral candidiasis, mouth dryness, anorexia, dysphagia,
flatulence, hepatitis, painful oral mucosa HEMIC/LYMPHATIC:
agranulocytosis, prolongation of prothrombin time, lymphadenopathy,
petechia METABOLIC/NUTRITIONAL: amylase increase,
lipase increase MUSCULOSKELETAL: arthralgia,
jaw, arm or back pain, joint stiffness, neck and chest pain, achiness,
flare up of gout, myasthenia gravis RENAL/UROGENITAL:
renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis,
renal calculi, frequent urination, acidosis, urethral bleeding, polyuria,
urinary retention, gynecomastia, candiduria, vaginitis, breast pain.
Crystalluria, cylindruria, hematuria and albuminuria have also been
reported RESPIRATORY: respiratory arrest, pulmonary
embolism, dyspnea, laryngeal or pulmonary edema, respiratory distress,
pleural effusion, hemoptysis, epistaxis, hiccough, broncospasm SKIN/HYPERSENSITIVITY: allergic reactions, anaphylactic
reactions including life-threatening anaphylactic shock, erythema
multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic
epidermal necrolysis, vasculitis, angioedema, edema of the lips, face,
neck, conjunctivae, hands or lower extremities, purpura, fever, chills,
flushing, pruritus, urticaria, cutaneous candidiasis, vesicles, increased
perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis,
burning, paresthesia, erythema, swelling, photosensitivity. (See WARNINGS.) SPECIAL SENSES: decreased visual acuity, blurred vision, disturbed
vision (flashing lights, change in color perception, overbrightness
of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus, nystagmus
chromatopsia, a bad taste In several instances,
nausea, vomiting, tremor, irritability, or palpitation were judged
by investigators to be related to elevated serum levels of theophylline
possibly as a result of drug interaction with ciprofloxacin. In randomized, double-blind controlled clinical trials
comparing ciprofloxacin (I.V. and I.V./P.O. sequential) with intravenous
beta-lactam control antibiotics, the CNS adverse event profile of
ciprofloxacin was comparable to that of the control drugs. Adverse Reactions in Pediatric
Patients: Information related to the adverse reactions of
ciprofloxacin 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 Hospira, Inc., is not labeled for pediatric use, except for inhalational
anthrax (post-exposure). Post-Marketing Adverse Events: The 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, anosmia, candiduria, cholesterol elevation (serum), confusion,
constipation, delirium, dyspepsia, dysphagia, erythema multiforme,
exfoliative dermatitis, fixed eruption, flatulence, glucose elevation
(blood), hemolytic anemia, hepatic failure, 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), phenytoin alteration (serum),
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 following the anthrax bioterror attacks
of October 2001. (See also INHALATIONAL
ANTHRAX - ADDITIONAL INFORMATION.) Adverse Laboratory Changes: The
most frequently reported changes in laboratory parameters with intravenous
ciprofloxacin therapy, without regard to drug relationship are listed
below: Other changes occurring infrequently were: decreased
leukocyte count, elevated atypical lymphocyte count, immature WBCs,
elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase
(��GT), decreased BUN, decreased uric acid, decreased total
serum protein, decreased serum albumin, decreased serum potassium,
elevated serum potassium, elevated serum cholesterol. Other changes
occurring rarely during administration of ciprofloxacin were: elevation
of serum amylase, decrease of blood glucose, pancytopenia, leukocytosis,
elevated sedimentation rate, change in serum phenytoin, decreased
prothrombin time, hemolytic anemia, and bleeding diathesis.
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Pregnant Women: THE SAFETY
AND EFFECTIVENESS OF CIPROFLOXACIN IN PREGNANT WOMEN, AND LACTATING
WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pregnancy and Nursing Mothers.) Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18
years of age) only for inhalational anthrax (post-exposure). Information
related to an additional use of ciprofloxacin in the pediatric population
is approved for Bayer Pharmaceutical Corporation's ciprofloxacin drug
products. An increased incidence of adverse events compared to controls,
including events related tojoints and/or surrounding tissues, has
been observed. (See ADVERSE REACTIONS.) Due to Bayer's marketing exclusivity rights, this drug product,
produced by Hospira Inc. is not labeled for pediatric use, except
for inhalational anthrax (post-exposure). 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 the 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 Disorders: Convulsions, increased intracranial pressure and toxic psychosis
have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin may also cause central nervous system (CNS) events including:
dizziness, confusion, tremors, hallucinations, depression, and, rarely,
suicidal thoughts or acts. These reactions may occur following the
first dose. If these reactions occur in patients receiving ciprofloxacin,
the drug should be discontinued and appropriate measures instituted.
As with all quinolones, ciprofloxacin should be used with caution
in patients with known or suspected CNS disorders that may predispose
to seizures or lower the seizure threshold (e.g., severe cerebral
arteriosclerosis, epilepsy), or in the presence of other risk factors
that may predispose to seizures or lower the seizure threshold (e.g.,
certain drug therapy, renal dysfunction). (See PRECAUTIONS: General, Information for Patients, Drug Interactions and ADVERSE REACTIONS.) Theophylline: SERIOUS AND FATAL
REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION
OF INTRAVENOUS CIPROFLOXACIN AND THEOPHYLLINE. These reactions
have included cardiac arrest, seizure, status epilepticus, and respiratory
failure. Although similar serious adverse events have been reported
in patients receiving theophylline alone, the possibility that these
reactions may be potentiated by ciprofloxacin cannot be eliminated.
If concomitant use cannot be avoided, serum levels of theophylline
should be monitored and dosage adjustments made as appropriate. Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
some following the first dose, have been reported in patients receiving
quinolone therapy. Some reactions were accompanied by cardiovascular
collapse, loss of consciousness, tingling, pharyngeal or facial edema,dyspnea, urticaria, and itching. Only a few patients had a history
of hypersensitivity reactions. Serious anaphylactic reactions require
immediate emergency treatment with epinephrine and other resuscitation
measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management, as clinically
indicated. Severe hypersensitivity reactions
characterized by rash, fever, eosinophilia, jaundice, and hepatic
necrosis with fatal outcome have also been reported extremely rarely
in patients receiving ciprofloxacin along with other drugs. The possibility
that these reactions were related to ciprofloxacin cannot be excluded.
Ciprofloxacin should be discontinued at the first appearance of a
skin rash or any other sign of hypersensitivity. Pseudomembranous Colitis: Pseudomembranous
colitis has been reported with nearly all antibacterial agents, including
ciprofloxacin, and may range in severity from mild to life-threatening.
Therefore, it is important to consider this diagnosis in patients
who present with diarrhea subsequent to the administration of antibacterial
agents. Treatment with antibacterial
agents alters the normal flora of the colon and may permit overgrowth
of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary
cause of���antibiotic-associated colitis.��� After the diagnosis of pseudomembranous colitis has been
established, therapeutic measures should be initiated. Mild cases
of pseudomembranous colitis usually respond to drug discontinuation
alone. In moderate to severe cases, consideration should be given
to management with fluids and electrolytes, protein supplementation,
and treatment with an antibacterial drug clinically effective against C. difficile colitis. Drugs that inhibit
peristalsis should be avoided. Peripheral neuropathy: Rare cases of sensory
or sensorimotor axonal polyneuropathy affecting small and/or large
axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness
have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms
of neuropathy including pain, burning, tingling, numbness, and/or
weakness, or is found to have deficits in light touch, pain, temperature,
position sense, vibratory sensation, and/or motor strength in order
to prevent the development of an irreversible condition. Tendon Effects: Ruptures
of the shoulder, hand, Achilles tendon or other tendons that required
surgical repair or resulted in prolonged disability have been reported
in patients receiving quinolones, including ciprofloxacin. Post-marketing
surveillance reports indicate that this risk may be increased in patients
receiving concomitant cortisteroids, especially the elderly. Ciprofloxacin
should be discontinued if the patient experiences pain, inflammation,
or rupture of a tendon. Patients should rest and refrain from exercise
until the diagnosis of tendonitis or tendon rupture has been excluded.
Tendon rupture can occur during or after therapy with quinolones,
including ciprofloxacin.
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Ciprofloxacin Injection, USP is indicated for the
treatment of infections caused by susceptible strains of the designated
microorganisms in the conditions and patient populations listed below
when the intravenous administration offers a route of administration
advantageous to the patient. Please see DOSAGE AND ADMINISTRATION for specific recommendations. Adult Patients: Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia), Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia
marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis. Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Proteus
mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also, Moraxella catarrhalis for the treatment
of acute exacerbations of chronic bronchitis. NOTE: Although effective in clinical trials, ciprofloxacin is not
a drug of first choice in the treatment of presumed or confirmed pneumonia
secondary to Streptococcus pneumoniae. Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae. Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Proteus
mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin
susceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus
epidermidis, or Streptococcus
pyogenes. Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa. Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis. Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae, or Moraxella catarrhalis. Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis. Empirical Therapy for Febrile
Neutropenic Patients in combination with piperacillin sodium.
(See CLINICAL STUDIES.) Pediatric Patients (1 to 17
years of age): Information related
to the treatment of pediatric patients for complicated urinary tract
infections and pyelonephritis is approved for Bayer Pharmaceutical
Corporation's ciprofloxacin drug products. 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, and ADVERSE REACTIONS.) Ciprofloxacin, like other fluoroquinolones,
is associated with arthropathy and histopathological changes in weight-bearing
joints of juvenile animals. (See ANIMAL PHARMACOLOGY.) Due to Bayer's
marketing exclusivity rights, this drug product, produced by Hospira,
Inc., is not labeled for pediatric use, except for inhalational anthrax
(post-exposure). 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 serve as a surrogate endpoint reasonably likely to predict
clinical benefit and provided the initial basis for approval of this
indication.Supportive clinical information for ciprofloxacin
for anthrax post-exposure prophylaxis was obtained during the anthrax
bioterror attacks of October 2001. (See also, INHALATIONAL ANTHRAX���ADDITIONAL
INFORMATION.) If anaerobic organisms
are suspected of contributing to the infection, appropriate therapy
should be administered. Appropriate culture
and susceptibility tests should be performed before treatment in order
to isolate and identify organisms causing infection and to determine
their susceptibility to ciprofloxacin. Therapy with Ciprofloxacin
Injection, USP 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 Injection,
USP and other antibacterial drugs, Ciprofloxacin Injection, USP should
be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria. When culture and susceptibility
information are available, they should be considered in selecting
or modifying antibacterial therapy. In the absence of such data, local
epidemiology and susceptibility patterns may contribute to the empiric
selection of therapy.
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Ciprofloxacin
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