Ciprofloxacin Hydrochloride (0823)

CATEGORIES, DRUG CLASSES, BRAND NAMES & COST OF THERAPY

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 TABLE 1 for the 250-1000 mg dose range.

TABLE 1 Dose Maximum Serum Concentration Area Under Curve (AUC) 250 mg 1.2 μg/ml 4.8 μg·h/ml 500 mg 2.4 μg/ml 11.6 μg·h/ml 750 mg 4.3 μg/ml 20.2 μg·h/ml 1000 mg 5.4 μg/ml 30.8 μg·h/ml

Maximum serum concentrations are attained 1-2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1 μg/ml, 0.2 μg/ml, 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 IV 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 IV 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 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. See TABLE 2.

TABLE 2 Steady-State Pharmacokinetic Parameters Following Multiple Oral and IV Doses   500 mg 400 mg 750 mg 400 mg Parameters q12h, PO q12h, IV q12h, PO q8h, IV AUC (μg·h/ml) 13.7* 12.7* 31.6† 32.9‡ Cmax (μg/ml) 2.97 4.56 3.59 4.07

* AUC(0-12h)

† AUC 24h = AUC(0-12h) × 2

‡ AUC 24h = AUC(0-8h) × 3

Ciprofloxacin extended-release tablets are formulated to release drug at a slower rate compared to immediate-release tablets. Approximately 35% of the dose is contained within an immediate-release component, while the remaining 65% is contained in a slow-release matrix.

Maximum plasma ciprofloxacin concentrations are attained between 1 and 4 hours after dosing with ciprofloxacin extended-release tablets. In comparison to the 250 and 500 mg ciprofloxacin immediate-release bid treatment, the C_max of ciprofloxacin extended-release tablets 500 and 1000 mg once daily are higher than the corresponding bid doses, while the AUCs over 24 hours are equivalent.

TABLE 3 compares the pharmacokinetic parameters obtained at steady-state for these 4 treatment regimens (500 mg qd ciprofloxacin extended-release tablets versus 250 mg bid ciprofloxacin immediate-release tablets and 1000 mg qd ciprofloxacin extended-release tablets versus 500 mg bid ciprofloxacin immediate-release) .

TABLE 3 Ciprofloxacin Pharmacokinetics (Mean ± SD) Following Ciprofloxacin Immediate-Release and Extended-Release Tablets Administration   Cmax (mg/L) AUC 0-24h (mg·h/L) T1/2 (h) Tmax (h)* Ciprofloxacin extended-release tablets 500 mg qd 1.59 ± 0.43 7.97 ± 1.87 6.6 ± 1.4 1.5 (1.0-2.5) Ciprofloxacin 250 mg bid 1.14 ± 0.23 8.25 ± 2.15 4.8 ± 0.6 1.0 (0.5-2.5) Ciprofloxacin extended-release tablets 1000 mg qd 3.11 ± 1.08 16.83 ± 5.65 6.31 ± 0.72 2.0 (1-4) Ciprofloxacin 500 mg qd 2.06 ± 0.41 17.04 ± 4.79 5.66 ± 0.89 2.0 (0.5-3.5)

* Median (range).

Distribution

The volume of distribution calculated for IV ciprofloxacin is approximately 2.1-2.7 L/kg. Studies with the oral and IV forms of ciprofloxacin have demonstrated penetration of ciprofloxacin into a variety of tissues. The binding of ciprofloxacin to serum proteins is 20-40%, 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.

Following administration of a single dose of ciprofloxacin extended-release tablets, ciprofloxacin concentrations in urine collected up to 4 hours after dosing averaged over 300 mg/L for both the 500 and 1000 mg tablets; in urine excreted from 12-24 hours after dosing, ciprofloxacin concentration averaged 27 mg/L for the 500 mg tablet, and 58 mg/L for the 1000 mg tablet.

Metabolism

Four (4) metabolites of ciprofloxacin were identified in human urine. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. The primary metabolites are oxociprofloxacin (M3) and sulfociprofloxacin (M2), each accounting for roughly 3-8% of the total dose. Other minor metabolites are desethylene ciprofloxacin (M1), and formylciprofloxacin (M4). The relative proportion of drug and metabolite in serum corresponds to the composition found in urine. Excretion of these metabolites was essentially complete by 24 hours after dosing.

Excretion

The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Approximately 40-50% 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 2 hours and are approximately 30 μg/ml at 8-12 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/min, exceeds the normal glomerular filtration rate of 120 ml/min. Thus, active tubular secretion would seem to play a significant role in its elimination. Coadministration 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 1-2% of the dose is recovered from the bile in the form of metabolites. Approximately 20-35% of an oral dose is recovered from the feces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination.

The elimination kinetics of ciprofloxacin are similar for the immediate-release and the ciprofloxacin extended-release tablet.

With oral administration, a 500 mg dose, given as 10 ml of the 5% ciprofloxacin oral suspension (containing 250 mg ciprofloxacin/5 ml) is bioequivalent to the 500 mg tablet. A 10 ml volume of the 5% ciprofloxacin oral suspension (containing 250 mg ciprofloxacin/5 ml) is bioequivalent to a 5 ml volume of the 10% ciprofloxacin oral suspension (containing 500 mg ciprofloxacin/5 ml).

Drug-Drug Interactions

When ciprofloxacin HCl 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 whereas there is no delay observed when ciprofloxacin oral suspension is given with food. The overall absorption of ciprofloxacin HCl tablet or ciprofloxacin oral suspension, however, is not substantially affected. The pharmacokinetics of ciprofloxacin given as the suspension are also not affected by food.

Extended-Release Tablets

Results of the pharmacokinetic studies demonstrate that ciprofloxacin extended-release tablets may be administered with or without food (e.g., high-fat and low-fat meals or under fasted conditions).

Previous studies with immediate-release ciprofloxacin have shown that 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. Absorption of ciprofloxacin is significantly reduced by concomitant administration of multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate, Videx (didanosine) chewable/buffered tablets or pediatric powder, or products containing calcium, iron, or zinc (see DRUG INTERACTIONS; PRECAUTIONS, Information for the Patient; and DOSAGE AND ADMINISTRATION).

Antacids

Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of ciprofloxacin by as much as 90%.

When ciprofloxacin extended-release tablets given as a single 1000 mg dose (twice the recommended daily dose) was administered 2 hours before, or 4 hours after a magnesium/aluminum-containing antacid (900 mg aluminum hydroxide and 600 mg magnesium hydroxide as a single oral dose) to 18 healthy volunteers, there was a 4% and 19% reduction, respectively, in the mean C_max of ciprofloxacin. The reduction in the mean AUC was 24% and 26%, respectively. Ciprofloxacin extended-release tablets should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, as well as sucralfate, Videx (didanosine) chewable/buffered tablets or pediatric powder, metal cations such as iron, and multivitamin preparations with zinc. Although ciprofloxacin extended-release tablets may be taken with meals that include milk, concomitant administration with dairy products or with calcium-fortified juices alone should be avoided, since decreased absorption is possible (see DRUG INTERACTIONS; PRECAUTIONS, Information for the Patient; and DOSAGE AND ADMINISTRATION).

Omeprazole

When ciprofloxacin extended-release tablets was administered as a single 1000 mg dose concomitantly with omeprazole (40 mg once daily for 3 days) to 18 healthy volunteers, the mean AUC and C_max of ciprofloxacin were reduced by 20% and 23%, respectively. The clinical significance of this interaction has not been determined. (See DRUG INTERACTIONS.)

Metronidazole

The serum concentrations of ciprofloxacin and metronidazole were not altered when these 2 drugs were given concomitantly.

Special Populations

Pharmacokinetic studies of the oral (single dose) and IV (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.)

Extended-Release Tablets

No dose adjustment is required for patients with uncomplicated urinary tract infections receiving 500 mg ciprofloxacin extended-release tablets. For complicated urinary tract infection and acute uncomplicated pyelonephritis, where 1000 mg is the appropriate dose, the dosage of ciprofloxacin extended-release tablets should be reduced to ciprofloxacin extended-release tablets 500 mg q24h in patients with creatinine clearance below 30 ml/min. (See DOSAGE AND ADMINISTRATION.)

In studies in patients with stable chronic 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. (See DOSAGE AND ADMINISTRATION.)

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.

Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between <10^-9 to 1 × 10^-6.

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 INDICATIONS AND USAGE.

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, Citrobacter diversus, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Salmonella typhi, Serratia marcescens, Shigella boydii, Shigella dysenteriae, Shigella flexneri, 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 CLINICAL STUDIES, 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, Aeromonas hydrophila, Edwardsiella tarda, Enterobacter aerogenes, Klebsiella oxytoca, Legionella pneumophila, Pasteurella multocida, Salmonella enteritidis, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, 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 Testing

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 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 criteria in TABLE 4.

For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae, and Neisseria gonorrhoeae,* see TABLE 4.

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

* 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,* see TABLE 5.

TABLE 5 MIC Interpretation ≤1 μg/ml Susceptible (S)

* 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,* see TABLE 6.

TABLE 6 MIC Interpretation ≤0.06 μg/ml Susceptible (S) 0.12-0.5 μg/ml Intermediate (I) ≥1 μg/ml Resistant (R)

* 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 MIC values in TABLE 7.

TABLE 7 Organism MIC E. faecalis ATCC 29212 0.25-2.0 μg/ml E. coli ATCC 25922 0.004-0.015 μg/ml H. influenzae* ATCC 49247 0.004-0.03 μg/ml N. gonorrhoeae† ATCC 49226 0.001-0.008 μg/ml P. aeruginosa ATCC 27853 0.25-1.0 μg/ml S. aureus ATCC 29213 0.12-0.5 μg/ml

* This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using Haemophilus Test Medium (HTM). 1

† This quality control range is applicable to only N. gonorrhoeae ATCC 49226 tested by an agar dilution procedure using GC agar base and 1% defined growth supplement.

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 procedure ² 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 aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae, and Neisseria gonorrhoeae,* see TABLE 8.

TABLE 8 Zone Diameter Interpretation ≥21 mm Susceptible (S) 16-20 mm Intermediate (I) ≤15 mm Resistant (R)

* These zone diameter standards are applicable only to tests performed for streptococci using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.

For testing Haemophilus influenzae and Haemophilus parainfluenzae,* see TABLE 9.

TABLE 9 Zone Diameter Interpretation ≥21 mm Susceptible (S)

* This zone diameter standard is applicable only to tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium (HTM) 2 .

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.

For testing Neisseria gonorrhoeae,* see TABLE 10.

TABLE 10 Zone Diameter Interpretation ≥41 mm Susceptible (S) 28-40 mm Intermediate (I) ≤27 mm Resistant (R)

* This zone diameter standard is applicable only to disk diffusion tests with GC agar base and 1% defined growth supplement.

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 μg ciprofloxacin disk should provide the following zone diameters in these laboratory test quality control strains. (See TABLE 11.)

TABLE 11 Organism Zone Diameter E. coli ATCC 25922 30-40 mm H influenzae* ATCC 49247 34-42 mm N. gonorrhoeae† ATCC 49226 48-58 mm P. aeruginosa ATCC 27853 25-33 mm S. aureus ATCC 25923 22-30 mm

* These quality control limits are applicable to only H. influenzae ATCC 49247 testing using Haemophilus Test Medium (HTM). 2

† These quality control limits are applicable only to tests conducted with N. gonorrhoeae ATCC 49226 performed by disk diffusion using GC agar base and 1% defined growth supplement.

Uncomplicated Cystitis

Two double-blind, controlled clinical studies of acute uncomplicated cystitis in women were performed in the US. At the 5-9 day post-therapy follow-up visit, the clinical resolution rates in the first study, which compared ciprofloxacin 100 mg bid for 3 days to ciprofloxacin 250 mg bid for 7 days, were 87% (82/94) and 94% (81/86), respectively. For E. coli, the bacteriological eradication rates for the first study were 91% (64/70) in the ciprofloxacin 100 mg regimen and 97% (67/69) in the cirpofloxacin 250 mg regimen. The second study's bacteriological eradication rates were 95% (117/123) for the ciprofloxacin 100 mg regimen and 98% (103/105) from the control regimen. Pooled eradicaiton rates for the ciprofloxacin 100 mg treatment arms were 100% (16/16) for S. saprophyticus.

Extended-Release Tablets

Ciprofloxacin extended-release tablets was evaluated for the treatment of uncomplicated urinary tract infections (acute cystitis) in a randomized, double-blind, controlled clinical trial conducted in the US. This study compared ciprofloxacin extended-release tablets (500 mg once daily for 3 days) with ciprofloxacin immediate-release tablets (ciprofloxacin 250 mg bid for 3 days). Of the 905 patients enrolled, 452 were randomly assigned to the ciprofloxacin extended-release treatment group and 453 were randomly assigned to the control group. The primary efficacy variable was bacteriological eradication of the baseline organism(s) with no new infection or superinfection at Test of Cure (Day 4-11 post-therapy).

The bacteriologic eradication and clinical success rates were similar between ciprofloxacin extended-release tablets and the control group. The eradication and clinical success rates and their corresponding 95% confidence intervals for the differences between rates (ciprofloxacin extended-release tablets minus control group) are given inTABLE 12.

TABLE 12     Ciprofloxacin extended-release tablets 500 mg qd × 3 Days Ciprofloxacin 250 mg bid × 3 Days Randomized patients 452 453 Per protocol patients* 199 223 Bacteriologic Eradication at TOC (n/N)† 188/199 (94.5%) 209/223 (93.7%)   CI [-3.5%, 5.1%] Bacteriologic Eradication (by organism) at TOC (n/N)‡   E coli 156/160 (97.5%) 176/181 (97.2%)   E faecalis 10/11 (90.9%) 17/21 (81.0%)   P mirabilis 11/12 (91.7%) 7/7 (100%)   S saprophyticus 6/7 (85.7%) 9/9 (100%) Clinical Response at TOC (n/N)§ 189/199 (95.0%) 204/223 (91.5%)   CI [-1.1%, 8.1%]

* The presence of a pathogen at a level of ≥105 CFU/ml was required for microbiological evaluability criteria, except for S. saprophyticus (≥104 CFU/ml).

† n/N=patients with baseline organism(s) eradicated and no new infections or superinfections/total number of patients.

‡ n/N=patients with specified baseline organism eradicated/patients with specified baseline organism.

§ n/N=patients with clinical success/total number of patients.

Complicated Urinary Tract Infections and Acute Uncomplicated Pyelonephritis

Extended-Release Tablets

Ciprofloxacin extended-release tablets was evaluated for the treatment of complicated urinary tract infections (cUTI) and acute uncomplicated pyelonephritis (AUP) in a randomized, double-blind, controlled clinical trial conducted in the US and Canada. The study enrolled 1042 patients (521 patients per treatment arm) and compared ciprofloxacin extended-release tablets (1000 mg once daily for 7-14 days) with immediate-release ciprofloxacin (500 mg bid for 7-14 days). The primary efficacy endpoint for this trial was bacteriologic eradication of the baseline organism(s) with no new infection or superinfection at 5-11 days post-therapy (test-of-cure or TOC) for the per protocol and modified intent-to-treat (MITT) populations.

The per protocol population was defined as patients with a diagnosis of cUTI or AUP, a causative organism(s) at baseline present at ≥ 10⁵ CFU/ml, no inclusion criteria violation, valid test-of-cure urine culture within the TOC window, an organism susceptible to study drug, no premature discontinuation or loss to follow-up, and compliance with the dosage regimen (among other criteria). More patients in the ciprofloxacin extended-release arm than in the control arm were excluded from the per protocol population and this should be considered in the interpretation of the study results. Reasons for exclusion with the greatest discrepancy between the 2 arms were no valid test of cure urine culture, an organism resistant to the study drug, and premature discontinuation due to adverse events.

An analysis of all patients with a causative organism(s) isolated at baseline and who received study medication, defined as the MITT population, included 342 patients in the ciprofloxacin extended-release arm and 324 patients in the control arm. Patients with missing responses were counted as failures in this analysis. In the MITT analysis of cUTI patients, bacteriologic eradication was 160/271 (59.0%) vs 156/248 (62.9%) in ciprofloxacin extended-release tablets and control arm, respectively [97.5% CI* (-13.5%, 5.7%)]. Clinical cure was 184/271 (67.9%) for ciprofloxacin extended-release tablets and 182/248 (73.4%) for control arm, respectively [97.5% CI* (-14.4%, 3.5%)]. Bacterial eradication in the MITT analysis of patients with AUP at TOC was 47/71 (66.2%) and 58/76 (76.3%) for ciprofloxacin extended-release tablets and control arm, respectively [97.5% CI* (-26.8%, 6.5%)]. Clinical cure at TOC was 50/71 (70.4%) for ciprofloxacin extended-release tablets and 58/76 (76.3%) for the control arm [97.5% CI* (- 22.0%, 10.4%)].

* Confidence interval of the difference in rates (ciprofloxacin extended-release tablets minus control).

In the per protocol population, the differences between ciprofloxacin extended-release tablets and the control arm in bacteriologic eradication rates at the TOC visit were not consistent between AUP and cUTI patients. The bacteriologic eradication rate for cUTI patients was higher in the ciprofloxacin extended-release tablets arm than in the control arm. For AUP patients, the bacteriologic eradication rate was lower in the ciprofloxacin extended-release arm than in the control arm. This inconsistency was not observed between the 2 treatment groups for clinical cure rates. Clinical cure rates were 96.1% (198/206) and 92.1% (211/229) for ciprofloxacin extended-release tablets and the control arm, respectively.

The bacterial eradication and clinical cure rates by infection type for ciprofloxacin extended-release tablets and the control arm at the TOC visit and their corresponding 97.5% confidence intervals for the differences between rates (ciprofloxacin extended-release tablets minus control arm) are given in TABLE 13 for the per protocol population analysis:

TABLE 13     Ciprofloxacin extended-release tablets 1000 mg qd Ciprofloxacin 500 mg bid Randomized patients 521 521 Per protocol patients* 206 229 cUTI Patients Bacteriologic eradication at TOC (n/N)† 148/166 (89.2%) 144/177 (81.4%)   CI [-0.7%, 16.3%] Bacteriologic eradication (by organism) at TOC (n/N)‡   E coli 91/94 (96.8%) 90/92 (97.8%)   K pneumoniae 20/21 (95.2%) 19/23 (82.6%)   E faecalis 17/17 (100%) 14/21 (66.7%)   P mirabilis 11/12 (91.6%) 10/10 (100%)   P aeruginosa 3/3 (100%) 3/3 (100%) Clinical cure at TOC (n/N)§   CI [-1.1%, 10.8%] AUP Patients Bacteriologic eradication at TOC (n/N)† 35/40 (87.5%) 51/52 (98.1%)   CI [-34.8%, 6.2%] Bacteriologic eradication of E. coli at TOC (n/N)‡ 35/36 (97.2%) 41/41 (100%) Clinical cure at TOC (n/N)§ 39/40 (97.5%) 50/52 (96.2%)   CI [-15.3%, 21.1%]

* Patients excluded from the per protocal population were primarily those with no causative organism(s) at baseline or no organism present at ≥105 CFU/ml at baseline, inclusion criteria violation, no valid test-of-cure urine culture within the TOC window, an organism resistant to study drug, premature discontinuation due to an adverse event, lost to follow-up, or noncompliance with dosage regimen (among other criteria).

† n/N=patients with baseline organism(s) eradicated and no new infections or superinfections/total number of patients.

‡ n/N=patients with specified baseline organism eradicated/patients with specified baseline organism.

§ n/N=patients with clinical success/total number of patients.

Of the 166 cUTI patients treated with ciprofloxacin extended-release tablets, 148 (89%) had the causative organism(s) eradicated, 8 (5%) had persistence, 5 (3%) patients developed superinfections and 5 (3%) developed new infections. Of the 177 cUTI patients treated in the control arm, 144 (81%) had the causative organism(s) eradicated, 16 (9%) patients had persistence, 3 (2%) developed superinfections and 14 (8%) developed new infections. Of the 40 patients with AUP treated with ciprofloxacin extended-release tablets, 35 (87.5%) had the causative organism(s) eradicated, 2 (5%) patients had persistence and 3 (7.5%) developed new infections. Of the 5 ciprofloxacin extended-release tablets AUP patients without eradication at TOC, 4 were considered clinical cures and did not receive alternative antibiotic therapy. Of the 52 patients with AUP treated in the control arm, 51 (98%) had causative organism(s) eradicated. One (1) patient (2%) had persistence.

Inhalational Anthrax — Additional Information

Tablets and Oral Suspension

The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving oral and IV regimens. (See DOSAGE AND ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human populations. The mean peak serum concentration achieved at steady-state in human adults receiving 500 mg orally every 12 hours is 2.97 μg/ml, and 4.56 μg/ml following 400 mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 μg/ml. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8.3 μg/ml and trough concentrations range from 0.09-0.26 μg/ml, following two 30 minute IV infusions of 10 mg/kg administered 12 hours apart. After the second IV infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6 μg/ml after the initial oral dose. Long-term safety data, including effects on cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For additional information, see PRECAUTIONS, Pediatric Use.) Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication. ⁴

A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD₅₀ [~5.5 × 10⁵ spores (range 5-30 LD₅₀)] of B. anthracis was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 μg/ml. In the animals studied, mean serum concentrations of ciprofloxacin achieved at expected T_max (1 hour post-dose) following oral dosing to steady-state ranged from 0.98-1.69 μg/ml. Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12-0.19 μg/ml. ⁵ Mortality due to anthrax for animals that received a 30 day regimen of oral ciprofloxacin beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The 1 ciprofloxacin-treated animal that died of anthrax did so following the 30 day drug administration period. ⁶

Ciprofloxacin is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below. Please see DOSAGE AND ADMINISTRATION for specific recommendations.

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, Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis.

Acute uncomplicated cystitis in females caused by Escherichia coli or Staphylococcus saprophyticus. (See DOSAGE AND ADMINISTRATION.)

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 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, 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, 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. (See DOSAGE AND ADMINISTRATION.)

Infectious diarrhea caused by Escherichia coli (enterotoxigenic strains), Campylobacter jejuni, Shigella boydii*, Shigella dysenteriae, Shigella flexneri, or Shigella sonnei* when antibacterial therapy is indicated.

*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.

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.

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 provide the basis for this indication ⁴ (see also CLINICAL STUDIES, 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 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.

Extended-Release Tablets

Ciprofloxacin extended-release tablets is indicated only for the treatment of urinary tract infections, including acute uncomplicated pyelonephritis, caused by susceptible strains of the designated microorganisms as listed below. Ciprofloxacin extended-release tablets and ciprofloxacin immediate-release tablets are not interchangeable. Please see DOSAGE AND ADMINISTRATION for specific recommendations.

Uncomplicated urinary tract infections (acute cystitis)  caused by Escherichia coli, Proteus mirabilis, Enterococcus faecalis, or Staphylococcus saprophyticus.*

Complicated urinary tract infections  caused by Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, Proteus mirabilis, or Pseudomonas aeruginosa.*

Acute uncomplicated pyelonephritis  caused by Eschericia coli.

*Treatment of infections due to this organism in this organ system was studied in fewer than 10 patients.

THE SAFETY AND EFFICACY OF CIPROFLOXACIN EXTENDED-RELEASE TABLETS IN TREATING INFECTIONS OTHER THAN URINARY TRACT INFECTIONS HAS NOT BEEN DEMONSTRATED.

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 extended-release tablets may be initiated before results of these tests are known; once results become available appropriate therapy should be continued. 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.

Non-FDA Approved Indications

Although not approved by the FDA, ciprofloxacin has been used in the treatment of multiple drug resistant tuberculosis, tularemia, and ulcerative colitis.

THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PEDIATRIC PATIENTS AND ADOLESCENTS (LESS THAN 18 YEARS OF AGE), —EXCEPT FOR USE IN INHALATIONAL ANTHRAX (POST-EXPOSURE), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pediatric Use , Pregnancy, Teratogenic Effects, Pregnancy Category C , and Nursing Mothers .) The 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.)

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 and Information for the Patient; DRUG INTERACTIONS and ADVERSE REACTIONS.)

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.

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. Oxygen, IV steroids, and airway management, including intubation, should be administered as indicated.

Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic necrosis with fatal outcome have also been rarely reported 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 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 1 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.

Achilles and other tendon ruptures that required surgical repair or resulted in prolonged disability have been reported with ciprofloxacin and other quinolones. Ciprofloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon.

Ciprofloxacin 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 3 months.

General

Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.

Quinolones, including ciprofloxacin, may also cause CNS events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See WARNINGS; PRECAUTIONS, Information for the Patient; and DRUG INTERACTIONS.)

Alteration of the dosage regimen is necessary for patients with impairment of renal function. (See DOSAGE AND ADMINISTRATION.)

Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has been observed in patients who are exposed to direct sunlight while receiving some members of the quinolone class of drugs. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs.

As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable during prolonged therapy.

Information for the Patient

Patients Should Be Advised:

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, didanosine chewable/buffered tablets or pediatric powder, or with other products containing calcium, iron or zinc should be avoided. Ciprofloxacin may be taken 2 hours before or 6 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.

To avoid excessive sunlight or artificial ultraviolet light while receiving ciprofloxacin and to discontinue therapy if phototoxicity occurs.

To discontinue treatment; rest and refrain from exercise; and inform their physician if they experience pain, inflammation, or rupture of a tendon.

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 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.

If the patient should forget to take ciprofloxacin extended-release tablets at the usual time, he/she may take the dose later in the day. Do not take more than 1 ciprofloxacin extended-release tablet/day even if a patient misses a dose. Swallow the ciprofloxacin extended-release tablet whole. DO NOT SPLIT, CRUSH, OR CHEW THE TABLET.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Eight 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 V79 Cell HGPRT Test (Negative).

Syrian Hamster Embryo Cell Transformation Assay (Negative).

Saccharomyces cerevisiae Point Mutation Assay (Negative).

Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative).

Rat Hepatocyte DNA Repair Assay (Positive).

Thus, 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 mice and rats have been completed. After daily oral doses of 750 mg/kg (mice) and 250 mg/kg (rats) were administered for up to 2 years, there was no evidence that ciprofloxacin had any carcinogenic or tumorigenic effects in these species.

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 5 times every 2 weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum recommended human dose based upon mg/m²), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16-32 weeks in mice treated concomitantly with UVA and other quinolones. ³

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 (1.0 times the highest recommended daily human dose of 1000 mg based upon body surface area) 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. ⁷

A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. ⁸ 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 musculoskelatal dysfunctions up to 1 year of age in the ciprofloxacin exposed children.

Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimetster exposures). ⁹ 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. ^7,8 However, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother (see WARNINGS).

Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.7 and 0.4 times the maximum daily human dose of 1000 mg based upon body surface area, respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, ciprofloxacin (30 and 100 mg/kg orally) produced gastrointestinal disturbances resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose. After IV administration of doses up to 20 mg/kg, no maternal toxicity was produced in the rabbit, and no embryotoxicity or teratogenicity was observed. (See WARNINGS.)

Nursing Mothers

Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients and adolescents less than 18 years of age have not been established, except for use in inhalational anthrax (post-exposure). Ciprofloxacin causes arthropathy in juvenile animals. (See WARNINGS.)

For the indication of 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 CLINICAL STUDIES, Inhalational Anthrax — Additional Information.

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 IV 10 mg/kg/dose q8h for 1 week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62 patients received the combination of ceftazidime IV 50 mg/kg/dose q8h and tobramycin IV 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.

In the study, injection site reactions were more common in the ciprofloxacin group (24%) than in the comparison group (8%). Other adverse events were similar in nature and frequency between treatment arms. Musculoskeletal adverse events 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. One (1) of 67 patients developed arthritis of the knee 9 days after a 10 day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities 8 months after treatment. However, the relationship of this event to the patient's course of ciprofloxacin can not be definitively determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as part of their underlying disease process.

Geriatric Use

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. In a large prospective, randomized ciprofloxacin extended-release tablets clinical trial in complicated urniary tract infections, 49% (509/1035) of the patients were 65 and over, while 30% (308/1035) were 75 and over. 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. The total drug exposure and maximum serum concentrations attained with ciprofloxacin extended-release tablets are similar to or less than the corresponding values achieved with 500 mg immediate-release ciprofloxacin, which is approved for use in renally impaired patients. Therefore, no reductions in dosage are required (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

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, didanosine chewable/buffered tablets or pediatric powder, 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 H₂-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 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.

Extended-Release Tablets

Absorption of the ciprofloxacin extended-release tablet was slightly diminished (20%) when given concomitantly with omeprazole. (See CLINICAL PHARMACOLOGY, Drug-Drug Interactions.)

Immediate-Release Tablets

During clinical investigation with the tablet, 2799 patients received 2868 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 3.5% of patients treated.

The most frequently reported events, drug related or not, were nausea (5.2%), diarrhea (2.3%), vomiting (2.0%), abdominal pain/discomfort (1.7%), headache (1.2%), restlessness (1.1%), and rash (1.1%).

Additional events that occurred in less than 1% of ciprofloxacin patients are listed below:

Body as a Whole: Foot pain.

Cardiovascular: Palpitation, atrial flutter, ventricular ectopy, syncope, hypertension, angina pectoris, myocardial infarction, cardiopulmonary arrest, cerebral thrombosis.

Central Nervous System: Dizziness, lightheadedness, insomnia, nightmares, hallucinations, manic reaction, irritability, tremor, ataxia, convulsive seizures, lethargy, drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression, paresthesia. (See above.) (See PRECAUTIONS.)

Gastrointestinal: Painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation, gastrointestinal bleeding. (See above.) Cholestatic jaundice has been reported.

Hemic/Lymphatic: Lymphadenopathy.

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: Pruritus, urticaria, photosensitivity, flushing, fever, chills, angioedema, edema of the face, neck, lips, conjunctivae or hands, cutaneous candidiasis, hyperpigmentation, erythema nodosum. (See above.) Allergic reactions ranging from urticaria to anaphylactic reactions have been reported. (See WARNINGS.)

Special Senses: Blurred vision, disturbed vision (change in color perception, overbrightness of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, 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 tablets (500 mg bid) to cefuroxime axetil (250-500 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.

Extended-Release Tablets

Clinical trials in patients with urinary tract infections enrolled 961 patients treated with 500 or 1000 mg ciprofloxacin extended-release tablets. Most adverse events reported were described as mild to moderate in severity and required no treatment. The overall incidence, type and distribution of adverse events were similar in patients receiving both 500 and 1000 mg of ciprofloxacin extended-release tablets. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug connot be directly compared to rates observed in clinical trials or another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studes does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

In the clinical trial of uncomplicated urinary tract infection, ciprofloxacin extended-release tablets (500 mg once daily) in 444 patients was compared tociprofloxacin immediate-release tablets (250 mg twice daily) in 447 patients for 3 days. Discontinuations due to adverse reactions thought to be drug-related occurred in 0.2% (1/444) of patients in the ciprofloxacin extended-release tablets arm and in 0% (0/447) of patients in the control arm.

In the clinical trial of complicated urinary tract infection and acute uncomplicated pyleonephritis, ciprofloxacin extended-release tablets (1000 mg once daily) in 517 patients was compared to ciprofloxacin immediate-release tablets (500 mg twice daily) in 518 patients for 7-14 days. Discontinuations due to adverse reactions thought to be drug-related occurred in 3.1% (16/517) of patients in the ciprofloxacin extended-release tablets arm and in 2.3% (12/518) of patients in the control arm. The most common reasons for discontinuation in the ciprofloxacin extended-release tablets arm were nausea/vomiting (4 patients) and dizziness (3 patients). In the control arm the most common reason for discontinuation was nausea/vomiting (3 patients).

In these clinical trials, the following events occurred in >2% of all ciprofloxacin extended-release tablets patients, regardless of drug relationship: nausea (4%), headache (3%), dizziness (2%), diarrhea (2%), vomiting (2%), and vaginal moniliasis (2%).

Adverse events, judged by investigators to be at least possibly drug-related, occurring in greater than or equal to 1% of ciprofloxacin extended-release treated patients were: nausea (3%), diarrhea (2%), headache (1%), dyspepsia (1%), dizziness (1%), and vaginal moniliasis (1%). Vomiting (1%) occurred in the 1000 mg group.

Additional uncommon events, judged by investigators to be at least possibly drug-related, that occurred in less than 1% of ciprofloxacin extended-release treated patients were:

Body as a Whole: Abdominal pain, asthenia, malaise, photosensitivity reaction.

Cardiovascular: Bradycardia, migraine, syncope.

Digestive: Anorexia, constipation, dry mouth, flatulence, liver function tests abnormal, thirst.

Hemic/Lymphatic: Prothrombin decreased.

Central Nervous System: Abnormal dreams, depersonalization, depression, hypertonia, incoordination, insomnia, somnolence, tremor, vertigo.

Metabolic: Hyperglycemia.

Skin/Appendages: Dry skin, maculopapular rash, pruritus, rash, skin disorder, urticaria, vesiculobullous rash.

Special Senses: Diplopia, taste perversion.

Urogenital: Dysmenorrhea, hematuria, kidney function abnormal, vaginitis.

Postmarketing Adverse Events

The following additional adverse events, in alphabetical order, regardless of incidence or relationship to drug, have been reported during clinical trials and from worldwide postmarketing experience in patients given ciprofloxacin (includes all formulations, all dosages, all drug therapy durations, and all indications): achiness, acidosis, agitation, agranulocytosis, allergic reactions (ranging from urticaria to anaphylactic reactions), anemia, angina pectoris, angioedema, anosmia, anxiety, arrhythmia, arthralgia, ataxia, atrial flutter, bleeding diathesis, blurred vision, bronchospasm, C. difficile associated diarrhea, candidiasis (cutaneous, oral), candiduria, cardiac murmur, cardiopulmonary arrest, cardiovascular collapse, cerebral thrombosis, chills, cholestatic jaundice, confusion, convulsion, delirium, depression, diplopia, drowsiness, dysphagia, dysphasia, dyspnea, edema (conjunctivae, face, hands, laryngeal, lips, lower extremities, neck, pulmonary), epistaxis, erythema multiforme, erythema nodosum, exfoliative dermatitis, fever, flushing, gastrointestinal bleeding, gout (flare up), gynecomastia, hallucinations, hearing loss, hematuria, hemolytic anemia, hemoptysis, hemorrhagic cystitis, hepatic necrosis, hiccup, hyperpigmentation, hypertension, hypotension, ileus, insomnia, interstitial nephritis, intestinal perforation, jaundice, joint stiffness, lethargy, lightheadedness, lymphadenopathy, malaise, manic reaction, mouth dryness, myalgia, myasthenia gravis (possible exacerbation), myocardial infarction, myoclonus, nephritis, nightmares, nystagmus, oral ulceration, pain (arm, back, breast, chest, epigastric, eye, foot, jaw, neck, oral mucosa), palpitation, pancreatitis, paranoia, paresthesia, perspiration (increased), phobia, pleural effusion, polyuria, postural hypotension, pseudomembranous colitis, pulmonary embolism, purpura, renal calculi, renal failure, respiratory arrest, respiratorydistress,restlessness,Stevens-Johnsonsyndrome, syncope, tachycardia, taste loss, tendinitis, tendon rupture, tinnitus, toxic epidermal necrolysis, toxic psychosis, tremor, unresponsiveness, urethral bleeding, urinary retention, urination (frequent), vaginal pruritus, vasculitis, ventricular ectopy, vesicles, visual acuity (decreased), visual disturbances (flashing lights, change in color perception, overbrightness of lights), weakness.

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.

Ciprofloxacin HCl tablets and oral suspension should be administered orally as described in TABLE 14.

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 intregrity 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 7-14 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, didanosine chewable/buffered tablets or pediatric powder for oral solution, or other products containing calcium, iron, or zinc.

TABLE 14 Dosage Guidelines Infection         Type or Severity Unit Dose Frequency Usual Durations* Urinary Tract   Acute uncomplicated 100 or 250 mg q12h 3 days   Mild/moderate 250 mg q12h 7-14 days   Severe/complicated 500 mg q12h 7-14 days Chronic Bacterial Prostatitis   Mild/moderate 500 mg q12h 28 days Lower Respiratory Tract   Mild/moderate 500 mg q12h 7-14 days   Severe/complicated 750 mg q12h 7-14 days Acute Sinusitis   Mild/moderate 500 mg q12h 10 days Skin and Skin Structure   Mild/moderate 500 mg q12h 7-14 days   Severe/complicated 750 mg q12h 7-14 days Bone and Joint   Mild/moderate 500 mg q12h ≥4 to 6 weeks   Severe/complicated 750 mg q12h ≥4 to 6 weeks Intra-Abdominal†   Complicated 500 mg q12h 7-14 days Infectious Diarrhea   Mild/moderate/severe 500 mg q12h 5-7 days Typhoid Fever   Mild/moderate 500 mg q12h 10 days Urethral and Cervical Gonococcal Infections   Uncomplicated 250 mg single dose single dose Inhalational Anthrax (Post-Exposure)‡   Adult 500 mg q12h 60 days   Pediatric 15 mg/kg/dose, not to exceed 500 mg/dose q12h 60 days

* Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have disappeared, except for inhalational anthrax (postexposure).

† Used in conjunction with metronidazole.

‡ Drug administration should begin as soon as possible after suspected or confirmed exposure. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely to predict clinical benefit. 4 For a discussion of ciprofloxacin serum concentrations in various human populations, see CLINICAL STUDIES, Inhalational Anthrax — Additional Information.

Patients whose therapy is started with ciprofloxacin HCl IV may be switched to ciprofloxacin HCl tablets or oral suspension when clinically indicated at the discretion of the physician. (See CLINICAL PHARMACOLOGY and TABLE 15 for the equivalent dosing regimens.)

TABLE 15 Equivalent AUC Dosing Regimens Ciprofloxacin HCl Oral Dosage Equivalent Ciprofloxacin HCl IV Dosage 250 mg tablet q12h 200 mg IV q12h 500 mg tablet q12h 400 mg IV q12h 750 mg tablet q12h 400 mg IV q8h

Impaired Renal Function

Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These alternate pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction. TABLE 16 provides dosage guidelines for use in patients with renal impairment; however, monitoring of serum drug levels provides the most reliable basis for dosage adjustment.

TABLE 16 Recommended Starting and Maintenance Doses for Patients With Impaired Renal Function Creatinine Clearance Dose >50 ml/min See usual dosage. 30-50 ml/min 250-500 mg q12h 5-29 ml/min 250-500 mg q18h Patients on hemodialysis or peritoneal dialysis 250-500 mg q24h (after dialysis)

Extended-Release Tablets

No dosage adjustment is required for patients with uncomplicated urinary tract infections receiving 500 mg ciprofloxacin extended-release tablets. For patients on hemodialysis or peritoneal dialysis, administer ciprofloxacin extended-release tablets after the dialysis procedure is completed. (See CLINICAL PHARMACOLOGY, Special Populations and PRECAUTIONS, Geriatric Use.)

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; however, patients should be carefully monitored and the serum ciprofloxacin concentration should be measured periodically. Peak concentrations (1-2 hours after dosing) should generally range from 2-4 μg/ml.

For patients with changing renal function or for patients with renal impairment and hepatic insufficiency, measurement of serum concentrations of ciprofloxacin will provide additional guidance for adjusting dosage.

Extended-Release Tablets

Ciprofloxacin extended-release tablets and ciprofloxacin immediate-release tablets are not interchangeable. Ciprofloxacin extended-release tablets should be administered orally once daily as described in TABLE 17.

TABLE 17 Dosage Guidelines Indication Unit Dose Frequency Usual Duration Uncomplicated urinary tract infection (acute cystitis) 500 mg q24h 3 days Complicated urinary tract infection 1000 mg q24h 7-14 days Acute uncomplicated pyelonephritis 1000 mg q24h 7-14 days

Ciprofloxacin extended-release tablets should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, as well as sucralfate, Videx (didanosine) chewable/buffered tablets or pediatric powder, metal cations such as iron, and multivitamin preparations with zinc. Although ciprofloxacin extended-release tablets may be taken with meals that include milk, concomitant administration with dairy products alone, or with calcium-fortified products should be avoided, since decreased absorption is possible. A 2 hour window between substantial calcium intake (>800 mg) and dosing with ciprofloxacin extended-release tablets is recommended. Ciprofloxacin extended-release tablets should be swallowed whole. DO NOT SPLIT, CRUSH, OR CHEW THE TABLET. (See CLINICAL PHARMACOLOGY, Drug-Drug Interactions; DRUG INTERACTIONS; and PRECAUTIONS, Information for the Patient.)

Impaired Hepatic Function

No dosage adjustment is required with ciprofloxacin extended-release tablets in patients with stable chronic cirrhosis. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully elucidated. (See CLINICAL PHARMACOLOGY, Special Populations.)

Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in beagles, removal of weight bearing from the joint reduced the lesions but did not totally prevent them.

Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy has been noted after single oral doses as low as 5 mg/kg. After 6 months of IV dosing at 10 mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration.

In dogs, ciprofloxacin at 3 and 10 mg/kg by rapid IV injection (15 sec) produces pronounced hypotensive effects. These effects are considered to be related to histamine release, since they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid IV injection also produces hypotension but the effect in this species is inconsistent and less pronounced.

In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.

Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals.

References

1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard NCCLS Document M7-A5 , Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.

2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests-Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.

3. Report presented at the FDA's Anti-Infective Drug and Dermatological Drug Products Advisory Committee meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA.

4. 21 CFR 314.510 (Subpart H — Accelerated Approval of New Drugs for Life-Threatening Illnesses).

5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7.

6. FriedlanderAM,etal. Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis 1993; 167: 1239-42.

7. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195.

8. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42(6):1336-1339.

9. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.

Absorption

Following 60 minute IV infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers, the mean maximum serum concentrations achieved were 2.1 and 4.6 μg/ml, respectively; the concentrations at 12 hours were 0.1 and 0.2 μg/ml, respectively.