(ciprofloxacin injection)
Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology (12.4)].
Absorption
Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers, the mean maximum serum concentrations achieved were 2.1 and 4.6 mcg/mL, respectively; the concentrations at 12 hours were 0.1 and 0.2 mcg/mL, respectively (Table 9).
| Time after starting the infusion | ||||||
| Dose | 30 minutes | 1 hour | 3 hour | 6 hour | 8 hour | 12 hour |
| 200 mg | 1.7 | 2.1 | 0.6 | 0.3 | 0.2 | 0.1 |
| 400 mg | 3.7 | 4.6 | 1.3 | 0.7 | 0.5 | 0.2 |
The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 mg to 400 mg administered intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th intravenous dose on an every 12 hour regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is within a range of 70 to 80% with no substantial loss by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg intravenous dose results in a Cmax similar to that observed with a 750-mg oral dose (Table 10). An infusion of 200 mg ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours.
* AUC0-12h x 2 | ||||
** AUC0-8h x 3 | ||||
| Parameters | 500 mg | 400 mg | 750 mg | 400 mg |
| every 12 hours, orally | every 12 hours, intravenously | every 12 hours, orally | every 8 hours, intravenously | |
| AUC (0-24h),ss (mcg⋅h/mL) |
27.4* | 25.4* | 31.6* | 32.9** |
| Cmax,ss(mcg/mL) | 2.97 | 4.56 | 3.59 | 4.07 |
Distribution
After intravenous administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations often exceed serum concentrations in both men and women, particularly in genital tissue including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.
Metabolism
After intravenous administration, three metabolites of ciprofloxacin have been identified in human urine which together account for approximately 10% of the intravenous dose. The metabolites have antimicrobial activity, but are less active than unchanged. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-administered drug [see Contraindications (4.2), Warnings and Precautions (5.10, 5.16) and Drug Interactions (7)].
Excretion
The serum elimination half-life is approximately 5 to 6 hours and the total clearance is around 35 L/hr. After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as unchanged drug. Following a 200- mg intravenous dose, concentrations in the urine usually exceed 200 mcg/mL 0 to 2 hours after dosing and are generally greater than 15 mcg/mL 8 to 12 hours after dosing. Following a 400 mg intravenous dose, urine concentrations generally exceed 400 mcg/mL 0 to 2 hours after dosing and are usually greater than 30 mcg/ mL 8 to 12 hours after dosing. The renal clearance is approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing.
Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after intravenous dosing, only a small amount of the administered dose (less than 1%) is recovered from the bile as unchanged drug. Approximately 15% of an intravenous dose is recovered from the feces within 5 days after dosing.
Elderly
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (older than 65 years) as compared to young adults. Although the Cmax is increased 16% to 40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant [see Use in Specific Populations (8.5)].
Renal Impairment
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required [see Use in Specific Populations (8.6) and Dosage and Administration (2.3)].
Hepatic Impairment
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, have not been fully studied.
Pediatrics
Table 11 summarizes pharmacokinetic parameters in pediatric patients aged less than 1 to less than 12 years of age receiving intravenous treatment.
*3xAUC0-8,ss | ||
| Age | auc0-24,ss (mg⋅h/L) | Cmax,ss (mg/L) |
| Less than 1 year | 30.9* | 2.8* |
| 1 to less than 2 years | 27.8* | 3.6* |
| 2 to less than 6 years | 28.9* | 2.7* |
| 6 to less than 12 years | 20.4* | 2.0* |
These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life in children is approximately 4 hours to 5 hours, and the bioavailability of the oral suspension is approximately 60%.
Drug-Drug Interactions
Metronidazole
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.
Tizanidine
In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin (500 mg twice a day for 3 days). Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Ropinirole
In a study conducted in 12 patients with Parkinson's disease who were administered 6 mg ropinirole once daily with 500 mg ciprofloxacin twice-daily, the mean Cmax and mean AUC of ropinirole were increased by 60% and 84%, respectively. Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16)].
Clozapine
Following concomitant administration of 250 mg ciprofloxacin with 304 mg clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
Sildenafil
Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg ciprofloxacin to healthy subjects, the mean Cmax and mean AUC of sildenafil were both increased approximately two-fold. Use sildenafil with caution when co-administered with ciprofloxacin due to the expected two-fold increase in the exposure of sildenafil upon co-administration of ciprofloxacin.
Duloxetine
In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in a 5-fold increase in mean AUC and a 2.5-fold increase in mean Cmax of duloxetine.
Lidocaine
In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with 500 mg ciprofloxacin twice daily resulted in an increase of lidocaine Cmax and AUC by 12% and 26%, respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible interaction with ciprofloxacin and an increase in adverse reactions related to lidocaine may occur upon concomitant administration.
Mechanism of Action
The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.
Mechanism of Resistance
The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin. Resistance to fluoroquinolones occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10 -9 to 1x10-6.
Cross Resistance
There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.
Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1)].
Gram-positive bacteria
Gram-negative bacteria
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ciprofloxacin against isolates of similar genus or organism group. However, the efficacy of ciprofloxacin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.
Gram-positive bacteria
Gram-negative bacteria
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.
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