Ciprofloxacin

CIPROFLOXACIN- ciprofloxacin hydrochloride tablet, film coated
McKesson Packaging Services a business unit of McKesson Corporation

WARNING

Fluoroquinolones, including ciprofloxacin, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (see WARNINGS).
Fluoroquinolones, including ciprofloxacin, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid ciprofloxacin in patients with known history of myasthenia gravis (see WARNINGS).

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 bacteria.

DESCRIPTION

Ciprofloxacin tablets, USP 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 molecular 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 molecular 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 film coated tablets are available in 250 mg, 500 mg, and 750 mg (ciprofloxacin equivalent) strengths. Ciprofloxacin tablets, USP are white to off-white. The inactive ingredients are microcrystalline cellulose, sodium starch glycolate, povidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, and titanium dioxide.

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 Concentration (mcg/mL)

Area Under Curve (AUC) (mcg•hr/mL)

250

1.2

4.8

500

2.4

11.6

750

4.3

20.2

1000

5.4

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 mcg/mL, respectively. The serum elimi‑nation 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 IV 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 IV Doses
a AUC 0-12h b AUC 24h=AUC0-12h x 2c AUC 24h=AUC0-8h x 3

Parameters

500 mg q12h, P.O.

400 mg q12h, IV

750 mg q12h, P.O.

400 mg q8h, IV

AUC (mcg•hr/mL)

13.7a

12.7a

31.6b

32.9c

Cmax (mcg/mL)

2.97

4.56

3.59

4.07

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 mcg/mL during the first two hours and are approximately 30 mcg/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.
With oral administration, a 500 mg dose, given as 10 mL of the 5% ciprofloxacin suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to the 500 mg tablet. A 10 mL volume of the 5% ciprofloxacin suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10% ciprofloxacin suspension (containing 500 mg ciprofloxacin/5mL).
Drug-Drug Interactions
When 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 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 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.)
Patients with Renal Impairment
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required. (See DOSAGE AND ADMINISTRATION.)
Patients with Hepatic Impairment
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.
Pediatrics
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4 months to 7 years, the mean Cmax was 2.4 mcg/mL (range: 1.5 to 3.4 mcg/mL) and the mean AUC was 9.2 mcg*h/mL (range: 5.8 to 14.9 mcg*h/mL). There was no apparent age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 mcg/mL (range: 4.6 to 8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2 mcg/mL (range: 4.7 to 11.8 mcg/mL) in 10 children between 1 and 5 years of age. The AUC values were 17.4 mcg*h/mL (range: 11.8 to 32 mcg*h/mL) and 16.5 mcg*h/mL (range: 11 to 23.8 mcg*h/mL) in the respective age groups. These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life in children is approximately 4 to 5 hours, and the bioavailability of the oral suspension is approximately 60%.
MICROBIOLOGY
Mechanism of Action

The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.
Mechanism of Resistance
The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin. Resistance to fluoroquinolones occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10-9 to 1×10-6.
Cross Resistance
There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.
Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGEsection of the package insert for ciprofloxacin tablets.
Gram-positive bacteria
Enterococcus faecalis (vancomycin-susceptible isolates only)
Staphylococcus aureus (methicillin-susceptible isolates only)
Staphylococcus epidermidis (methicillin-susceptible isolates only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible isolates only)
Streptococcus pyogenes
Gram-negative bacteria
Campylobacter jejuni Proteus mirabilis
Citrobacter koseri (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. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ciprofloxacin (≤1 mcg/mL). However, the efficacy of ciprofloxacin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
Gram-positive bacteria
Staphylococcus haemolyticus (methicillin-susceptible isolates only)
Staphylococcus hominis (methicillin-susceptible isolates only)
Bacillus anthracis
Gram-negative bacteria
Acinetobacter Iwoffi Pasteurella multocida
Aeromonas hydrophila Salmonella enteritidis
Edwardsiella tarda Vibrio cholerae
Enterobacter aerogenes Vibrio parahaemolyticus
Klebsiella oxytoca Vibrio vulnificus
Legionella pneumophila Yersinia enterocolitica
Susceptibility Test Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

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 test method (broth and/or agar).1,3,4 The MIC values should be interpreted according to criteria provided in Table 1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,3,4 This procedure uses paper disks impregnated with 5 mcg ciprofloxacin to test the susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive criteria are provided in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Ciprofloxacin

MIC (mcg/mL)

Zone Diameter (mm)

Bacteria

S

I

R

S

I

R

Enterobacteriaceae

≤1

2

≥4

≥21

16-20

≤15

Enterococcus faecalis

≤1

2

≥4

≥21

16-20

≤15

Staphylococcus aureus

≤1

2

≥4

≥21

16-20

≤15

Staphylococcus epidermidis

≤1

2

≥4

≥21

16-20

≤15

Staphylococcus saprophyticus

≤1

2

≥4

≥21

16-20

≤15

Pseudomonas aeruginosa

≤1

2

≥4

≥21

16-20

≤15

Haemophilus influenzae a

≤1

-

-

≥21

-

-

Haemophilus parainfluenzae a

≤1

-

-

≥21

-

-

Salmonella typhi

≤0.06

0.12-0.5

≥1

≥31

21-30

≤20

Streptococcus pneumoniae

≤1

2

≥4

≥21

16-20

≤15

Streptococcus pyogenes

≤1

2

≥4

≥21

16-20

≤15

Neisseria gonorrhoeae

≤0.06

0.12-0.5

≥1

≥41

28-40

≤27

Bacillus anthracis a

≤0.25

-

-

-

-

-

S=Susceptible, I=Intermediate, and R=Resistant. a The current absence of data on resistant isolates precludes defining any results other than “Susceptible”. If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.

A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. 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 that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3,4 Standard ciprofloxacin powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the ciprofloxacin 5 mcg disk the criteria in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Ciprofloxacin

Bacteria

MIC Range (mcg/mL)

Zone Diameter (mm)

Enterococcus faecalis ATCC 29212

0.25–2

-

Escherichia coli ATCC 25922

0.004–0.015

30–40

Haemophilus influenzae ATCC 49247

0.004–0.03

34–42

Pseudomonas aeruginosa ATCC 27853

0.25–1

25–33

Staphylococcus aureus ATCC 29213

0.12–0.5

-

Staphylococcus aureus ATCC 25923

-

22–30

Neisseria gonorrhoeae ATCC 49226

0.001–0.008

48–58

Campylobacter jejuni ATCC 33560

0.06–0.25 and 0.03–0.12

-

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