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Proquin XR (Ciprofloxacin Hydrochloride) - Description and Clinical Pharmacology

 
 



Proquin® XR
(ciprofloxacin hydrochloride)
Extended-Release Tablets, 500 mg

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Proquin XR and other antibacterial drugs, Proquin XR should be used only to treat uncomplicated urinary tract infections that are strongly suspected to be caused by bacteria.

DESCRIPTION

Proquin XR (ciprofloxacin hydrochloride) extended-release tablets contain ciprofloxacin hydrochloride, a synthetic broad-spectrum fluoroquinolone antimicrobial agent for oral administration.

Ciprofloxacin hydrochloride is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid hydrochloride. The molecular weight of the monohydrate is 385.82. It is a faintly yellowish to light yellow crystalline substance and its chemical structure is as follows:

Proquin XR is available as 500 mg (ciprofloxacin equivalent) tablets, utilizing AcuForm™ delivery technology. Proquin XR tablets are blue film-coated and oval-shaped. The inactive ingredients are povidone, magnesium stearate, polyethylene oxide, and film coating (Opadry® Blue).

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)
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.
Mean (%CV)
AUC0-24h (mcg.hr/mL) 7.67 (25) 7.83 (16)
Cmax (mcg/mL) 0.82 (28) Cmax1 0.57 (25)b
Cmax2 0.93 (27)
Cmin (mcg/mL) 0.06 (42) 0.14 (29)
Mean ± SD
Tmax (hr) 6.1 ± 2.6 Tmax1 2.5 ± 1.2c
Tmax2 2.5 ± 1.4

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 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.

Multivalent 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.

MICROBIOLOGY

Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive organisms. 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.

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
    Escherichia coli
    Klebsiella pneumoniae

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 in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-negative microorganisms
    Proteus mirabilis

Susceptibility Tests

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 following criteria:

For testing Enterobacteriaceae:

MIC (mcg/mL) Interpretation
≤ 1 Susceptible (S)
2 Intermediate (I)
≥ 4 Resistant (R)

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.

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 following MIC values:

Microorganism MIC Range (mcg/mL)
Escherichia coli ATCC 25922 0.004-0.015
Staphylococcus aureus ATCC 29213 0.12-0.5

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 procedure2 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 following criteria:

For testing Enterobacteriaceae:

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

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-mcg ciprofloxacin disk should provide the following zone diameters in these laboratory quality control strains:

Microorganism Zone Diameter (mm)
Escherichia coli ATCC 25922 30-40
Staphylococcus aureus ATCC 25923 22-30

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.

CLINICAL STUDIES

Proquin XR 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 (CIPRO® 250 mg twice daily for 3 days). Of the 1,037 patients enrolled, 524 were randomly assigned to the Proquin XR treatment group and 513 were randomly assigned to the control group. A total of 272 (52%) patients in the Proquin XR group and 251 (49%) in the CIPRO 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 the following table:

Bacteriological Eradication and Clinical Cure Rates at the Test-of-Cure (TOC) Visit
Proquin XR 500 mg
qd x 3 Days
CIPRO 250 mg
bid x 3 Days
* Number of patients with specified baseline organism eradicated / Number of per-protocol patients with specified baseline organism.
Randomized Patients 524 513
Per Protocol Patients 272 (52%) 251 (49%)
Bacteriologic Eradication with no new infection at TOC 212 / 272 (78%) 193 / 251 (77%)
(-6.2%, 8.2%)
Clinical Response at TOC 233 / 272 (86%) 216 / 251 (86%)
(-6.4%, 5.6%)
Bacteriologic Eradication by organism*
E. coli
K. pneumonia
211 / 222 (95%)
11 / 12 (92%)
184 / 202 (91%)
10 / 13 (77%)

The bacteriological eradication rates for baseline organisms at the TOC visit were 93% (254/272) for Proquin XR and 90% (225/251) for CIPRO. Of the patients with their baseline organism eradicated, new infections were detected in 42/254 (16.5%) Proquin XR-treated patients and 32/225 (14.2%) CIPRO-treated patients at the TOC visit. Gram-negative rods were responsible for new infections in 10 Proquin XR-treated patients and 7 CIPRO-treated patients, and Enterococcus species were isolated in 24 Proquin XR-treated patients, and 20 CIPRO-treated patients.

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