Prescription Drug Information: Ciprofloxacin (Page 7 of 10)

12.3 Pharmacokinetics

Absorption

The absolute bioavailability of ciprofloxacin when given as an oral tablet is approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations and area under the curve are shown in the chart for the 250 mg to 1000 mg dose range ( Table 10).

Table 10: Maximum Serum Concentrations and Areas Under the Curve
Dose (mg) Maximum Serum Concentration (mcg/mL) Area Under Curve (AUC) (mcg•hr/mL)
250 1.2 4.8
500 2.4 11.6
750 4.3 20.2
1000 5.4 30.8

Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 mcg/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations increase proportionately with doses up to 1000 mg.

A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg Ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a C max similar to that observed with a 400 mg intravenous 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 ( Table 11).

Table 11: Steady-state Pharmacokinetic Parameters Following Multiple Oral and IV Doses

1. AUC 0–12h

2. AUC 24h = AUC 0–12h x 2

3. AUC 24h = AUC 0–8h x 3

Parameters 500 mg 400 mg 750 mg 400 mg
every 12 hours, orally every 12 hours, intravenous every 12 hours, orally. every 8 hours, intravenous
AUC (mcg•hr/mL) 13.7 1 12.7 1 31.6 2 32.9 3
C max (mcg/mL) 2.97 4.56 3.59 4.07

Food

When Ciprofloxacin Tablet is given concomitantly with food, there is a delay in the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather than 1 hour. The overall absorption of Ciprofloxacin Tablet, however, is not substantially affected. The pharmacokinetics of ciprofloxacin given as the suspension are also not affected by food. Avoid concomitant administration of Ciprofloxacin with dairy products (like milk or yogurt) or calcium-fortified juices alone since decreased absorption is possible; however, Ciprofloxacin may be taken with a meal that contains these products.

Distribution

The binding of ciprofloxacin to serum proteins is 20% to 40% which is not likely to be high enough to cause significant protein binding interactions with other drugs.

After oral administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations often exceed serum concentrations in both men and women, particularly in genital tissue including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.

Metabolism

Four metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. 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 ( 5.9, 5.15), and Drug Interactions ( 7)].

Excretion

The serum elimination half-life in subjects with normal renal function is approximately 4 hours.

Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200 mcg/mL during the first two hours and are approximately 30 mcg/mL at 8 to 12 hours after dosing. The urinary excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination. Co-administration of probenecid with ciprofloxacin results in about a 50% reduction in the ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation.

Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged drug. An additional 1% to 2% of the dose is recovered from the bile in the form of metabolites. Approximately 20% to 35% of an oral dose is recovered from the feces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination.

Specific Populations

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 C max 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

Following a single oral dose of 10 mg/kg Ciprofloxacin suspension to 16 children ranging in age from 4 months to 7 years, the mean C max was 2.4 mcg/mL (range: 1.5 mcg/mL to 3.4 mcg/mL) and the mean AUC was 9.2 mcg*hr/mL (range: 5.8 mcg*hr/mL to 14.9 mcg*h/mL). There was no apparent age-dependence, and no notable increase in C max or AUC upon multiple dosing (10 mg/kg three times a day). In children with severe sepsis who were given Ciprofloxacin IV (10 mg/kg as a 1-hour intravenous infusion), the mean C max was 6.1 mcg/mL (range: 4.6 mcg/mL to 8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2 mcg/mL (range: 4.7 mcg/mL to 11.8 mcg/mL) in 10 children between 1 year and 5 years of age. The AUC values were 17.4 mcg*hr/mL (range: 11.8 mcg*hr/mL to 32 mcg*hr/mL) and 16.5 mcg*hr/mL (range: 11 mcg*hr/mL to 23.8 mcg*hr/mL) in the respective age groups. These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life in children is approximately 4 hours –5 hours, and the bioavailability of the oral suspension is approximately 60%.

Drug-Drug Interactions

Antacids

Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of ciprofloxacin by as much as 90% [see Dosage and Administration ( 2.4) and Drug Interactions ( 7)].

Histamine H2-receptor antagonists

Histamine H 2 -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.

Tizanidine

In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (C max 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 C max 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 ( 5.9)].

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 C max 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 C max of duloxetine.

Lidocaine

In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with Ciprofloxacin 500 mg twice daily resulted in an increase of lidocaine C max 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.

Metoclopramide

Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in a shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin.

Omeprazole

When Ciprofloxacin was administered as a single 1000 mg dose concomitantly with omeprazole (40 mg once daily for three 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.

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