CLINICAL PHARMACOLOGY
Absorption
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 tablets. Proquin XR should be administered with a main meal of the day, preferably the evening meal; if Proquin XR is given while fasting, the bioavailability will be lowered substantially. Administration of Proquin XR 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. The following table presents the pharmacokinetic parameters obtained at steady state for Proquin XR 500 mg qd versus CIPRO 250 mg bid.
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) |
| Mean (%CV) |
| AUC 0-24 h (mcg.hr/mL) | 7.67 (25) | 7.83 (16) |
| C max (mcg/mL) | 0.82 (28) | Cmax,1 0.57 (25)b
Cmax,2 0.93 (27)
|
| C min (mcg/mL) | 0.06 (42) | 0.14 (29) |
| Mean ± SD |
| T max (hr) | 6.1 ± 2.6 | 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 CIPRO bid.
Cmax2 = peak concentration after the morning dose of CIPRO bid.
c Tmax1 = time of peak concentration after the evening dose CIPRO bid.
Tmax2 = time of peak concentration after the morning dose CIPRO bid.
Distribution
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.
Metabolism
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.
Elimination
The plasma elimination half-life of ciprofloxacin in healthy volunteers following a Proquin XR 500 mg dose was approximately 4.5 hours. Following a 500 mg oral dose of Proquin XR, 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, 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 qd and CIPRO 250 mg bid are shown in the following table:
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) |
| 3 | 67 (28) |
| CIPRO 250 mg twice daily | 1 | 79 (32) |
| 3 | 75 (24) |
The renal clearance of ciprofloxacin following administration of Proquin XR, 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 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.
Drug Interactions
Antacids: The interaction of Proquin XR (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 was given 2 hours after antacids and 6 hours before antacids, the Cmax values were similar to those when Proquin XR was given alone and AUC values were reduced by approximately 10%. When Proquin XR 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 should be given either 2 hours after or at least 4 hours before antacids (see PRECAUTIONS, Drug Interactions , and Information for Patients).
Caffeine: Some quinolones, including ciprofloxacin also decrease caffeine clearance and inhibit the formation of paraxanthine after caffeine administration. (See PRECAUTIONS: Drug Interactions)
Calcium-containing beverages: Concomitant administration of ciprofloxacin with milk products or calcium-fortified juices alone should be avoided since decreased absorption is possible. (See PRECAUTIONS: Drug Interactions and Information for Patients, and DOSAGE AND ADMINISTRATION)
Histamine H 2 -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.
M ultivalent cation-containing products : Concomitant administration of ciprofloxacin with sucralfate, VIDEX® (didanosine) chewable/buffered tablets, metal cations such as iron and calcium, and multivitamin preparations with zinc should be avoided. (See PRECAUTIONS: Drug Interactions and Information for Patients)
Omeprazole: When Proquin XR 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 was administered alone. Omeprazole should be taken as directed and Proquin XR should be taken with a main meal of the day, preferably the evening meal. (See PRECAUTIONS: Drug Interactions and Information for Patients)
Probenecid: Co-administration of probenecid with fluoroquinolones results in a reduction in the renal clearance and an increase in their concentrations in the systemic circulation.
Theophylline: Previous studies with quinolones, including ciprofloxacin, have shown that concomitant administration of these drugs with theophylline decreases the clearance of theophylline resulting in elevated serum theophylline levels and increased risk of a patient developing central nervous system (CNS) or other adverse reactions. (See WARNINGS , PRECAUTIONS: Drug Interactions)
Warfarin: Ciprofloxacin and other 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. The co-administration of single doses of Proquin XR and 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 were not significantly altered by ciprofloxacin co-administration, the half-life of R-warfarin was statistically significantly prolonged (P=0.029). (See PRECAUTIONS: Drug Interactions)
Special Populations
Elderly: When a single 500 mg dose of Proquin XR 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 PRECAUTIONS: Geriatric Use)
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 is required for patients with uUTI and mild to moderate renal impairment. The efficacy of Proquin XR has not been studied in patients with severe renal impairment. (See DOSAGE AND ADMINISTRATION)
Altered Liver Function: 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 DOSAGE AND ADMINISTRATION)
Pediatrics: The pharmacokinetics of Proquin XR have not been studied in pediatric populations.
ANIMAL PHARMACOLOGY
There were no indications of gastrointestinal or other toxic effects due to oral administration of Proquin XR tablets to male and female beagle dogs at doses up to 1000 mg/day for 28 days (approximately 2.6- and 4.9-fold [male and female dogs, respectively] the recommended therapeutic dose based upon AUC measures of systemic exposure).
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested. (See WARNINGS)
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.
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.
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.
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