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Mechanism of Action
Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology].
When Proquin XR is administered with food, approximately 87% of ciprofloxacin is gradually released from the tablet over a 6-hour period. When administered following a meal maximum plasma ciprofloxacin concentrations are attained approximately 4.5-7 hours after dosing with Proquin XR (ciprofloxacin hcl) tablets. Proquin XR (ciprofloxacin hcl) should be administered with a main meal of the day, preferably the evening meal; if Proquin XR (ciprofloxacin hcl) is given while fasting, the bioavailability will be lowered substantially. Administration of Proquin XR (ciprofloxacin hcl) with a standardized meal (1000 calories, 50% fat) increased the Cmax and AUC0-24h by approximately 120% and 170%, respectively, compared to administration under fasting conditions; the mean Tmax was prolonged from 2.3 hours to 4.5 hours. Table 2 presents the pharmacokinetic parameters obtained at steady state for Proquin XR 500 mg once daily versus ciprofloxacin immediate-release tablets 250 mg twice daily.
Table 2: Steady-State Pharmacokinetics for Ciprofloxacin
in Plasma of Healthy Subjects (Day 3)a
|Pharmacokinetic Parameters||Proquin XR 500 mg Tablets (qd) (n=27)||CIPRO 250 mg Tablets (bid) (n=27)|
|AUC0-24h (mcg.hr/mL)||7.67 (25)||7.83 (16)|
|Cmax (mcg/mL)||0.82 (28)||Cmax,1 0.57 (25)b Cmax,2 0.93 (27)|
|Cmin (mcg/mL)||0.06 (42)||0.14 (29)|
|Tmax (hr)||6.1 ±Tmax1 2.5||Tmax1 2.5 ± 1.2 c Tmax2 2.5 ± 1.4|
|a both treatments were administered
following a standardized meal (approximately 1000 calories, 50% fat).
b Cmax1 = peak concentration after the evening dose of ciprofloxacin immediate-release tablets twice daily. Cmax2 = peak concentration after the morning dose of ciprofloxacin immediate-release tablets twice daily.
c Tmax1 = time of peak concentration after the evening dose ciprofloxacin immediate-release tablets twice daily. Tmax2 = time of peak concentration after the morning dose ciprofloxacin immediate-release tablets twice daily.
The in vitro binding of ciprofloxacin to plasma proteins over a concentration ranging from 0.9 to 30 micromolar is 9.9% to 36.6%, which is not likely to cause clinically significant protein binding interactions with other drugs.
Four metabolites of ciprofloxacin have been identified in human urine and feces. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. The metabolites are desethyleneciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and formylciprofloxacin (M4), which account for approximately 11% of the total dose.
The plasma elimination half-life of ciprofloxacin in healthy volunteers following a Proquin XR (ciprofloxacin hcl) 500 mg dose was approximately 4.5 hours. Following a 500 mg oral dose of Proquin XR (ciprofloxacin hcl) , 26.9% was excreted in the urine over 24 hours as unchanged drug for both formulations.
Following administration of a single 500 mg dose of Proquin XR (ciprofloxacin hcl) , approximately 41% of the oral dose was excreted into the urine over 96 hours as unchanged drug and metabolites. The urinary excretion of ciprofloxacin was virtually complete within 24 hours after dosing. Urinary excretion is a main route of elimination of ciprofloxacin and its urinary concentrations relative to the MICs of the bacterial species may be important to understanding the efficacy of ciprofloxacin for the treatment of urinary tract infections. The mean urinary ciprofloxacin concentration after dosing with Proquin XR 500 mg once daily and ciprofloxacin immediate-release tablets 250 mg twice daily are shown in Table 3.
Table 3: Mean Urinary Concentrations of Ciprofloxacin
|Treatment||Day||Mean (%CV) urinary ciprofloxacin concentration over 24 hours (mcg/mL)|
|Proquin XR 500 mg once daily||1||71 (41)|
|Ciprofloxacin immediate-release tablets 250 mg twice daily||1||79 (32)|
The renal clearance of ciprofloxacin following administration of Proquin XR (ciprofloxacin hcl) , which is approximately 304 - 383 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.
Approximately 43% of the oral dose of Proquin XR (ciprofloxacin hcl) is recovered from the feces as unchanged drug and metabolites within 7 days after dosing. This may arise from either biliary clearance or transintestinal elimination.
Elderly: When a single 500 mg dose of Proquin XR (ciprofloxacin hcl) was administered to elderly subjects ( > 65 years) Cmax and AUC values were increased by approximately 24% and 20% respectively, compared to younger subjects from a reference study. This can be at least partially attributed to decreased renal clearance in the elderly. However, in elderly subjects, the percentage of the ciprofloxacin dose excreted in the urine was 11% lower as compared to younger subjects. The elimination half-life was not significantly prolonged in elderly subjects (4.9 hours) compared to healthy young subjects (4.5 hours). These differences are not considered clinically significant [see Use In Specific Populations].
Renal Impairment: After receiving a single dose of Proquin XR 500 mg, the ciprofloxacin AUC0-24h in subjects with mild renal impairment (CLcr = 51-80 mL/min; n=10) and moderate renal impairment (CLcr = 30-50 mL/min; n=10) were 42% and 54% greater, respectively, compared to subjects with normal renal function (CLcr > 80 mL/min; n=10). The elimination half-life of ciprofloxacin in patients with mild and moderate renal impairment was approximately 1.7 times longer as compared to the control group (7.8 - 7.5 hours versus 4.5 hours). In patients with end-stage renal disease (CLcr < 10 mL/min), the half-life of ciprofloxacin is approximately doubled compared to subjects with normal renal function. No dose adjustment of Proquin XR (ciprofloxacin hcl) is required for patients with uUTI and mild to moderate renal impairment. The efficacy of Proquin XR (ciprofloxacin hcl) has not been studied in patients with severe renal impairment [see Use In Specific Populations].
Hepatic Impairment: In studies in patients with stable chronic cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The pharmacokinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, has not been fully elucidated [see Use In Specific Populations].
Pediatrics: The pharmacokinetics of Proquin XR (ciprofloxacin hcl) have not been studied in pediatric populations [see Use In Specific Populations].
Antacids: The interaction of Proquin XR (ciprofloxacin hcl) (administered as a single 1000 mg [2 x 500 mg] dose) and magnesium/aluminum-containing antacids (900 mg aluminum hydroxide and 600 mg magnesium hydroxide administered as a single oral dose) was evaluated in healthy volunteers. When Proquin XR (ciprofloxacin hcl) was given 2 hours after antacids and 6 hours before antacids, the Cmax values were similar to those when Proquin XR (ciprofloxacin hcl) was given alone and AUC values were reduced by approximately 10%. When Proquin XR (ciprofloxacin hcl) was given 4 hours before antacids, Cmax was reduced by approximately 11% and AUC was reduced by approximately 22%. Thus, to minimize the effect of antacids on the absorption of ciprofloxacin, Proquin XR (ciprofloxacin hcl) should be given either 2 hours after or at least 4 hours before antacids [see DRUG INTERACTIONS].
Histamine H2-receptor antagonists: Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin.
Metronidazole: The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.
Omeprazole: The rate and extent of absorption of ciprofloxacin was bioequivalent when Proquin XR (ciprofloxacin hcl) was given alone or when Proquin XR (ciprofloxacin hcl) was given 2 hours after omeprazole at the dose that maximally suppresses gastric acid secretion. When Proquin XR (ciprofloxacin hcl) was administered following a meal as a single 1000 mg dose (2 x 500 mg), 2 hours after the third dose of omeprazole (given 40 mg once daily for three days) to 27 healthy volunteers, the mean AUC and Cmax of ciprofloxacin were bioequivalent to the mean AUC and Cmax values when Proquin XR (ciprofloxacin hcl) was administered alone. Omeprazole should be taken as directed and Proquin XR (ciprofloxacin hcl) should be taken with a main meal of the day, preferably the evening meal.
Warfarin: The co-administration of single doses of Proquin XR (ciprofloxacin hcl) and warfarin (Coumadin® 7.5 mg) did not result in significant changes in the pharmacokinetics of ciprofloxacin nor did it significantly affect the pharmacodynamics of S-warfarin and R-warfarin. Although the Cmax and AUC of the two warfarin enantiomers and the elimination half-life of S-warfarin, the pharmacologically active enantiomer, were not significantly altered by ciprofloxacin coadministration, the half-life of R-warfarin was statistically significantly prolonged (P=0.029). When Proquin XR and oral anticoagulants are administered concomitantly, prothrombin time or other suitable coagulation tests should be monitored [see DRUG INTERACTIONS].
Mechanism of Action
The bactericidal action of ciprofloxacin results from inhibition of topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases) which are required for bacterial DNA replication, transcription, repair and recombination.
The mechanism of action of quinolones, including ciprofloxacin, is different from that of other antimicrobial agents such as beta-lactams, macrolides, tetracyclines, or aminoglycosides; therefore, organisms resistant to these drugs may be susceptible to ciprofloxacin. There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. Resistance to ciprofloxacin in vitro develops slowly (multiple step mutation). Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10-9 to 1x10-6.
Activity in vitro and in vivo
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive organisms. Ciprofloxacin is 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 MIC by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following organisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
Aerobic gram-negative microorganisms
The following in vitro data are available, but their clinical significance is unknown:
Ciprofloxacin exhibits in vitro MICs of 1 mcg/mL or less against most ( > 90%) strains of the following microorganisms; however, the safety and effectiveness of Proquin XR (ciprofloxacin hcl) in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Aerobic gram-negative microorganisms
Interpretive criteria for urinary isolates have not been established for Proquin XR. Interpretive criteria established based on systemic drug levels may not be appropriate for uncomplicated urinary tract infections.
- Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 4.
- 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-mcg ciprofloxacin to test the susceptibility
of microorganisms to ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-mcg ciprofloxacin disk should be interpreted according to the f criteria outlined in Table 4. 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.
Table 4: Susceptibility Interpretive Criteria for Ciprofloxacin
|Pathogen||Minimum Inhibitory Concentrations (mcg/mL)||Disk Diffusion (zone diameter in mm)|
|Enterobacteriaceae||≤ 1||2||≥ 4||≥ 21||16-20||≤ 15|
|S=Susceptible, I=Intermediate, and R=Resistant|
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration 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 concentration usually achievable; other therapy should be selected.
- Quality Control:
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. For dilution technique, standard ciprofloxacin powder should give the MIC values provided in Table 4. For diffusion technique, the 5 mcg ciprofloxacin disk should provide zone diameters provided in Table 5.
Table 5: Quality Control for Susceptibility Testing
|Microorganism||Microorganism QC Number||MIC (mcg/mL)||Disk Diffusion (zone diameter in mm)|
|Escherichia coli||ATCC 25922||0.004-0.015||30-40|
|Staphylococcus aureus||ATCC 29213||0.12-0.5||Not applicable|
|Staphylococcus aureus||ATCC 25923||Not applicable||22 – 30|
Gastrointestinal or other toxic effects were not observed in male and female beagle dogs following oral administration of Proquin XR (ciprofloxacin hcl) tablets at doses up to 1,000 mg/day for 28 consecutive days (approximately 3 and 5 times the human therapeutic dose based upon AUC comparisons to male and female dogs, respectively).
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with the fluoroquinolone class of drugs. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals. In contrast, crystalluria is rare in man since human urine is typically acidic [see ADVERSE REACTIONS].
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effects of quinolones [see DRUG INTERACTIONS].
Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals. There was no indication of ocular toxicity in the dog study cited above.
Uncomplicated Urinary Tract Infections
Proquin XR (ciprofloxacin hcl) was evaluated for the treatment of uncomplicated urinary tract infections (acute cystitis) in a randomized, double-blind, controlled trial conducted in the US. This study compared Proquin XR 500 mg once daily for 3 days with ciprofloxacin immediate-release tablets. Of the 1,037 patients enrolled, 524 were randomly assigned to the Proquin XR (ciprofloxacin hcl) treatment group and 513 were randomly assigned to the control group. A total of 272 (52%) patients in the Proquin XR (ciprofloxacin hcl) group and 251 (49%) in the control group were evaluable for efficacy and included in the Per-Protocol population. The primary efficacy variable was bacteriologic eradication of the baseline organism(s) with no new infection at the Test-of-Cure (TOC) visit (Day 4 to 11 post-therapy).
The bacteriological eradication and clinical success rates were similar for both treatment groups. The eradication and clinical success rates and their corresponding 95% confidence intervals for the differences between rates (Proquin XR minus control group) are given in Table 6.
Table 6: Bacteriological Eradication and Clinical Cure Rates
at the Test-of-Cure (TOC) Visit
|Proquin XR 500 mg once daily for 3 days||Ciprofloxacin immediate- release tablet 250 mg twice daily for 3 days|
|qd x 3 Days||bid x 3 Days|
|Per Protocol Patients||272 (52%)||251 (49%)|
|Bacteriologic Eradication with no new infection at TOC||212 / 272 (78%)||193 / 251 (77%)|
|Clinical Response at TOC||233 / 272 (86%)||216 / 251 (86%)|
|Bacteriologic Eradication by organism*|
|E. coli||211 / 222 (95%)||184 / 202 (91%)|
|K. pneumoniae||11 / 12 (92%)||10 / 13 (77%)|
|*Number of patients with specified baseline organism eradicated /Number of per-protocol patients with specified baseline organism.|
The bacteriological eradication rates for baseline organisms at the TOC visit were 93% (254/272) for Proquin XR and 90% (225/251) for ciprofloxacin immediate-release tablets. Of the patients with their baseline organism eradicated, new infections were detected in 42/254 (16%) Proquin XR-treated patients and 32/225 (14%) ciprofloxacin-treated patients at the TOC visit. Gram-negative rods were responsible for new infections in 10 Proquin XR-treated patients and 7 ciprofloxacin-treated patients, and Enterococcus species were isolated in 24 Proquin XR-treated patients, and 20 ciprofloxacin-treated patients.
Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. Eight Edition. Approved Standard CLSI Document M7-A8, Vol. 29, No. 2, CLSI, Wayne, PA, January, 2009.
Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests. Tenth Edition. Approved Standard CLSI Document M2-A10, Vol. 29, No. 1, CLSI, Wayne, PA, January, 2009.
Last reviewed on RxList: 4/19/2011
This monograph has been modified to include the generic and brand name in many instances.
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