Ciprofloxacin: Package Insert and Label Information

CIPROFLOXACIN- ciprofloxacin hydrochloride tablet
Lake Erie Medical DBA Quality Care Products LLC

WARNING:

Fluoroquinolones, including CIPROFLOXACIN TABLETS USP, 250 mg, 500 mg and 750 mg, 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).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ciprofloxacin Tablets USP, 250 mg, 500 mg and 750 mg and other antibacterial drugs Ciprofloxacin Tablets USP, 250 mg, 500 mg and 750 mg should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Ciprofloxacin Hydrochloride Tablets USP, 250 mg, 500 mg and 750 mg are synthetic broad spectrum antimicrobial agents 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 molecular weight of 385.8. Its empirical formula is C17 H18 FN3 O3 •HCl•H2 O and its chemical structure is as follows:

Chemical Structure


Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17 H18 FN3 O3 and its molecular weight is 331.4. It is a faintly yellowish to light yellow crystalline substance and its chemical structure is as follows:

Chemical Structure

Ciprofloxacin Tablets USP are film-coated tablets and are available in 250 mg, 500 mg and 750 mg (ciprofloxacin equivalent) strengths. Ciprofloxacin Tablets are white to slightly yellowish. The inactive ingredients are pregelatinized starch, microcrystalline cellulose, colloidal silicon dioxide, crospovidone, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol and purified water.

CLINICAL PHARMACOLOGY

Absorption:

Ciprofloxacin 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.

Dose (mg) Maximum Serum Concentrations (μg/mL) Area Under Curve(AUC) (μg•hr/mL)
250 500 750 1000 1.2 2.4 4.3 5.4 4.8 11.6 20.2 30.8

Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 μg/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 Cmax 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.

Steady-state Pharmacokinetic Parameters Following Multiple Oral and I.V. Doses
Parameters AUC (μg•hr/mL) Cmax (μg/mL) 500 mg q12h, P.O. 13.7a 2.97 400 mg q12h, I.V. 12.7a 4.56 750 mg q12h, P.O. 31.6b 3.59 400 mg q8h, I.V. 32.9c 4.07

a AUC 0-12h
b AUC 24h=AUC0-12h x 2
c AUC 24h=AUC0-8h x 3

Distribution:

The 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.

Metabolism:

Four 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).

Excretion:

The 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 Interactions:

When Ciprofloxacin Tablets USP, 250 mg, 500 mg and 750 mg 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 Tablets USP, 250 mg, 500 mg and 750 mg 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 Populations:

Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65 years) as compared to young adults. Although the Cmax is increased 16- 40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. (See PRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. 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.

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 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 insert for Ciprofloxacin Hydrochloride Tablets USP, 250mg, 500mg and 750mg.

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 pyogenes

Aerobic 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 Iwoffii 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 Techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted according to the following criteria:For testing aerobic microorganisms other than Haemophilus influenzae , Haemophilus parainfluenzae , and Neisseria gonorrhoeae a:

MIC (μg/mL) Interpretation
≤ 1 Susceptible (S)
2 Intermediate (I)
≥ 4 Resistant (R)


a These interpretive standards are applicable only to broth microdilution susceptibility tests with streptococci using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.For testing Haemophilus influenzae and Haemophilus parainfluenzae b:

MIC (μg/mL) Interpretation
≤ 1 Susceptible (S)


b This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium.1
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.For testing Neisseria gonorrhoeae c:

MIC (μg/mL) Interpretation
≤ 0.06 Susceptible (S)
0.12 – 0.5 Intermediate (I)
≥ 1 Resistant (R)


c This interpretive standard is applicable only to agar dilution test with GC agar base and 1% defined growth supplement.
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:

Organism MIC (μg/mL)
E. faecalis ATCC 29212 0.25 – 2
E. coli ATCC 25922 0.004 – 0.015
H. influenzae a ATCC 49247 0.004 – 0.03
P. aeruginosa ATCC 27853 0.25 – 1.0
S. aureus ATCC 29213 0.12 – 0.5
C. jejuni b ATCC 33560 0.06 – 0.25 and 0.03 – 0.12
N. gonorrhoeae c ATCC 49226 0.001– 0.008


a This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using Haemophilus Test Medium (HTM)1.
b C. jejuni ATCC 33560 tested by broth microdilution procedure using cation adjusted Mueller Hinton broth with 2.5-5% lysed horse blood in a microaerophilic environment at 36-37°C for 48 hours and for 42°C at 24 hours2 , respectively.
c N. gonorrhoeae ATCC 49226 tested by agar dilution procedure using GC agar and 1% defined growth supplement in a 5% CO2 environment at 35-37°C for 20-24 hours3.

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